3-Ureidobenzodiazepinones useful as antagonists of CCK or of gastrin

ABSTRACT

This invention relates to compounds having formula (I), ##STR1## wherein R 1  is a hydrogen or halogen atom or an alkyl, alkoxy, alkylthio, nitro, hydroxy or cyano radical; R 2  is an alkyl radical or a chain --CH(R 5 )--CO--R 6  ; R 3  is (a) a phenyl radical substituted by one or a plurality of substituents selected amongst the radicals -alk-SO 3  H, -alk-PO 3  H 2 , --CH═NOH, --CH--NO-alk-COOX, --S-alk-COOX, --SO-alk-COOX, --SO 2  -alk-COOX, --CH═CH--COOX, -alk-CO--NHOH, --C(═NOH)--COOX, -alk-N(OH)--CO-alk,-alk-SO 2  H, --CH═CH--SO 3  H, --C(COOX)═N--O-alk-COOX, tetrazolyalkyle or a group having a formula (I) or (b) a ring having the formula (A) ##STR2## wherein R 9  is a radical ═NOX, ═NO-alk-COOX, ═CH--COOX, -alk-COOX, -alk-SO 2  H or -alk-S) 3  H, R 10  is an oxygen or sulfur atom or a methylene or alkylimino radical and R 11  is a methylene or ethylene radical, R 4  is a pyridyle or phenyl radical optionally substituted by one or a plurality of substituents selected amongst halogen atoms or the alkyl, alkoxy, hydroxy, carboxy, nitro and --CO--NR 6  radicals, alk is an alkyl or alkylene radical and X is a hydrogen atom or an alkyl radical. The invention also discloses the salts thereof, their preparation and medicaments containing them.

DESCRIPTION OF THE INVENTION

The present invention relates to derivatives of formula: ##STR3## theirsalts, their preparation and medicaments containing them.

In the formula (I)

R₁ represents a hydrogen or halogen atom or an alkyl, alkoxy, alkylthio,nitro, hydroxyl or cyano radical,

R₂ represents an alkyl radical or a --CH(R₅)--CO--R₆ chain in which R₅represents a hydrogen atom or an alkyl, alkoxycarbonyl or phenyl radicalwhich is optionally substituted (by one or more substituents chosen fromamongst halogen atoms and alkyl, alkoxy, alkylthio and nitro radicals)and R₆ represents an alkoxy radical, a cycloalkoxy radical which isoptionally substituted (by at least one alkyl radical), acycloalkylalkoxy, phenylalkoxy, polyfluoroalkoxy or cinnamyloxy radicalor an --NR₇ R₈ radical in which R₇ and R₈, which are identical ordifferent, represent a hydrogen atom or an alkyl radical, a phenylradical which is optionally substituted (by one or more substituentschosen from amongst halogen atoms and alkyl, alkoxy and alkylthioradicals), or a cycloalkylalkyl, cycloalkyl, indanyl or phenylalkylradical or else R₇ and R₈, together with the nitrogen atom to which theyare attached, form a saturated or unsaturated monocyclic or polycyclicheterocycle containing 4 to 9 carbon atoms and one or more hetero atoms(O, S, N) and optionally substituted by one or more alkyl, alkoxy,alkoxycarbonyl, dialkylcarbamoyl or phenyl radicals or byspiromonocyclic cyclic system formed by combination of an atom of theheterocycle with 4 to 5 other carbon atoms, one or more of the latteroptionally being replaced by hetero atoms (O, S, N),

R₃ represents (a) a phenyl radical substituted by one or moresubstituents chosen from amongst -alk-SO₃ H, -alk-PO₃ H₂, --CH═NOH,--CH═NO-alk-COOX, --S-alk-COOX, -SO-alk-COOX, --SO₂ -alk-COOX,--CH═CH--COOX, -alk-CO--NHOH, --C(═NOH)--COOX, -alk-N(OH)--CO-alk,-alk-SO₂ H, --CH═CH--SO₃ H, --C(COOX)═N--O-alk-COOX and tetrazolylalkylradicals or a group of formula: ##STR4## or (b) a cyclic system offormula: ##STR5## in which R₉ represents an ═NOX, ═NO-alk-COOX,═CH--COOX, -alk-COOX, -alk-SO₂ H or -alk-SO₃ H radical, R₁₀ representsan oxygen or sulphur atom or a methylene or alkylimino radical and R₁₁represents a methylene or ethylene radical,

R₄ represents a pyridyl or phenyl radical which is optionallysubstituted by one or more substituents chosen from amongst halogenatoms and alkyl, alkoxy, hydroxyl, carboxyl, nitro and --CO--NR₆radicals,

alk represents an alkyl or alkylene radical,

X represents a hydrogen atom or an alkyl radical.

In the above definitions and those which will be mentioned below, unlessstated otherwise the alkyl, alkylene and alkoxy radicals and the alkyl,alkylene and alkoxy portions contain 1 to 4 carbon atoms in a straightor branched chain, and the cycloalkyl radicals and portions contain 3 to12 carbon atoms.

When R₇ and R₈, together with the nitrogen atom to which they areattached, form a heterocycle, the latter is preferably a piperidino,1-perhydroazepinyl, 1,2,3,6-tetrahydro-1-pyridyl,1,2,3,4-tetrahydro-1-quinolyl, 1-pyrrolidinyl,1,2,3,4-tetrahydro-2-isoquinolyl, morpholino, thiomorpholino or1-indolyl cyclic system, it being possible for these cyclic systems tobe optionally substituted by one or more alkyl radicals.

The compounds of formula (I) comprise one or more asymmetric centerswhich give isomeric forms. The racemates and the enantiomers of thesecompounds are likewise a part of the invention.

The compounds of formula (I) can be prepared by reaction of a reactivederivative of carbamic acid, optionally obtained in situ by the actionof a reactive derivative of carbonic acid chosen from amongstN,N'carbonyldiimidazole, phosgene, trichloromethyl chloroformate,bis(trichloromethyl) carbonate and p-nitrophenyl chloroformate on aderivative of formula: ##STR6## in which R₁, R₂ and R₄ have the samemeanings as in the formula (I), with a derivative of formula:

    H.sub.2 N--R.sub.3                                         (III)

in which R₃ has the same meanings as in the formula (I) or, when R₃comprises a COOH, PO₃ H₂, SO₂ H or SO₃ H radical, a salt of such acompound.

This reaction is preferably carried out in an inert solvent such astetrahydrofuran, dimethylformamide, a chlorinated solvent (chloroform or1,2-dichloroethane, for example) or an aromatic solvent (benzene ortoluene, for example), at a temperature of between 20° C. and theboiling point of the solvent. The salts used are preferably a salt withan alkali metal (sodium or potassium, for example) or atetraalkylammonium salt (tetrabutylammonium, for example).

The derivatives of formula (II) can be obtained by application oradaptation of the methods described in the U.S. Pat. Nos. 3,371,084,3,652,634, the patent applications DE 3,907,390, NL 327,674, EP 349,949and EP 385,735, by I. FRYER, Bicyclic diazepines, diazepine with anadditionnal ring, John Wiley & Sons Inc., M.G. BOCK et al., J. Org.Chem., 52, 3232 (1987) and in the examples.

The derivatives of formula (III) are commercially available or can beobtained by application or adaptation of the methods described by R.SCHROTER, Methoden der organischen Chemie (Methods of OrganicChemistry), Houben-Weyl, Volume XI/1, 360 and in the examples.

The compounds of formula (I) can also be prepared by the action of aderivative of formula: ##STR7## in which R₁, R₂ and R₄ have the samemeanings as in the formula (I), on an amine of formula (III) or, when R₃comprises a COOH, PO₃ H₂, SO₂ H or SO₃ H radical, a salt of such acompound.

This reaction is generally carried out in an inert solvent such astetrahydrofuran, dimethylformamide, a chlorinated solvent (chloroform or1,2-dichloroethane, for example) or an aromatic solvent (benzene ortoluene, for example), at a temperature of between 10° C. and theboiling point of the solvent.

The derivatives of formula (IV) can be obtained by the action of aderivative of formula (II) on a reactive derivative of carbonic acidsuch as phosgene, trichloromethyl chloroformate or bis(trichloromethyl)carbonate.

This reaction is carried out in an inert solvent such as toluene, at atemperature of between -30° C. and 110° C.

The compounds of formula (I), with the exception of those for which R₃represents either a phenyl radical substituted by -alk-PO₃ H₂, --CH═NOH,--CH═NO-alk-COOX, --S-alk-COOX, --SO-alk-COOX, --SO₂ -alk-COOX,--CH═CH--COOX, -alk-CO--NHOH, -alk-N(OH)--CO-alk, --C(═NOH)--COOX,--C(COOX)═NO-alk-COOX, -alk-SO₂ H or tetrazolylalkyl, or a cyclic systemof formula (A) in which R₉ represents an ═NOX, ═NO-alk-COOX, ═CH--COOX,-alk-COOX or -alk-SO₂ H radical and X represents a hydrogen atom, canalso be prepared by the action of a derivative of formula (II) on anisocyanate of formula:

    OCN--R.sub.3                                               (V)

in which R₃ has the same meanings as above.

This reaction is generally carried out in an inert solvent such astetrahydrofuran, dimethylformamide, a chlorinated solvent (chloroform or1,2-dichloroethane, for example) or an aromatic solvent (benzene ortoluene, for example), at a temperature of between 10° C. and theboiling point of the solvent.

The isocyanates of formula (V) can be obtained by application oradaptation of the method described by R. RICHTER et al., The Chemistryof Cyanate and their Thio Derivatives, S. PATAI, part 2, Wiley New York(1977) and the methods described in the examples.

The compounds of formula (I) for which R₃ represents a phenyl radicalsubstituted by an --SO-alk-COOX or SO₂ -alk-COOX radical and Xrepresents an alkyl radical can be prepared by oxidation ofcorresponding compounds of formula (I) for which R₃ represents a phenylradical substituted by an --S-alk-COOX radical.

This oxidation is generally carried out with the aid of Oxone®(potassium peroxymonosulphate) marketed by Aldrich, in an alcohol suchas methanol or a methanol/water mixture, at a temperature near to 25° C.

The compounds of formula (I) for which R₃ represents either a phenylradical substituted by --CH═N--O-alk-COOX, --S-alk-COOX, --SO-alk-COOX,--C(═NOH)--COOX, --SO₂ -alk-COOX, --CH═CH--COOX or--C(COOH)═N--O--alk-COOX, or a cyclic system of formula (A) in which R₉represents a radical ═CH-COOX, ═NO-alk-COOX or -alk-COOX and Xrepresents a hydrogen atom, can also be prepared by cleavage of acorresponding eater.

This cleavage is carried out by any method known to the person skilledin the art for converting an ester to an acid. When an alkyl ester isused, it is advantageous to work with the aid of a base such as lithiumhydroxide, sodium hydroxide or potassium hydroxide, in an inert solventsuch as tetrahydrofuran, dioxane, pyridine, water, an alcohol or amixture of these solvents, at a temperature of between 20° C. and theboiling point of the solvent, or with the aid of trifluoroacetic acid,optionally in an inert solvent such as a chlorinated solvent(dichloromethane, chloroform or 1,2-dichloroethane, for example), at atemperature of between 20° C. and the boiling point of the solvent. Whena benzyl ester is used, it is advantageous to work with the aid ofhydrogen, in the presence of a transition metal, in an inert solventsuch as an alcohol, at a temperature of between 20° and 40° C. oraccording to the method described by T. TSUJI et al., TetrahedronLetters, 2793 (1979).

The compounds of formula (I) for which R₃ represents a cyclic system (A)in which R₉ represents an ═NOX or ═NO-alk-COOX radical can also beprepared by the action of a derivative of formula: ##STR8## in which R₁,R₂, R₄, R₁₀ and R₁₁ have the same meanings as in the formula (I), on aderivative of formula:

    H.sub.2 NOZ                                                (VII)

in which Z represents a hydrogen atom or an alkyl or -alk-COOX radical.

This reaction is preferably carried out in a solvent such as pyridine,water or a mixture of these solvents, at the boiling point of thereaction medium.

It is understood by the person skilled in the art that for the purposeof carrying out the processes according to the invention described aboveit may be necessary to introduce amino, hydroxyl or carboxyl protectivegroups in order to avoid secondary reactions such as those described byT. W. GREENE, Protective Groups in Organic Synthesis, John Wiley, NewYork. The amino functions can be blocked, for example, in the form oftert-butyl or methyl carbamates and then regenerated with the aid ofiodotrimethylsilane or in the form of benzyl carbamates and thenregenerated by hydrogenation after having carried out the processaccording to the invention. The hydroxyl functions can be blocked, forexample, in the form of benzoate and then regenerated by hydrolysis inalkaline medium after having carried out the process according to theinvention.

The enantiomers of the compounds of formula (I) containing at least oneasymmetric site can be obtained by resolution of the racemates, forexample by chromatography on a chiral column according to W. H. PIRKLEet al., Asymmetric Synthesis, Vol. 1, Academic Press (1983) or on asilica column coated with cellulose tris(3,5-dimethylphenylcarbamate)such as those described in J. Am Chem. Soc., 106, 5357 (1984), elutingwith a suitable solvent such as ethanol or an ethanol/hexane mixture orby synthesis starting from chiral precursors.

The compounds of formula (I) can be purified by the usual known methods,for example by crystallization, chromatography or extractions.

The compounds of formula (I) can optionally be converted into additionsalts with an inorganic or organic acid by the action of such an acid inan organic solvent such as an alcohol, a ketone, an ether or achlorinated solvent.

The compounds of formula (I) containing an acidic radical can also beconverted into metallic salts or into addition salts with nitrogen basesaccording to methods known per se. These salts can be obtained by theaction of a metallic base (alkaline or alkaline earth metal, forexample), ammonia, a tetraalkylammonium, an amine or a salt of anorganic acid on a compound of formula (I), in a solvent. The salt formedis separated by the usual methods.

These salts are also a part of the invention.

Examples of pharmaceutically acceptable salts which can be mentioned areaddition salts with inorganic or organic acids (such as the acetates,propionates, succinates, benzoates, fumarates, maleates, oxalates,methanesulphonates, isethionates, theophyllineacetates, salicylates,methylene-bis-β-oxynaphthoates, hydrochlorides, sulphates, nitrates andphosphates), salts with alkali metals (sodium, potassium or lithium) orwith alkaline earth metals (calcium or magnesium), the ammonium salts orthe salts of nitrogen bases (ethanolamine, trimethylamine, methylamine,benzylamine, N-benzyl-β-phenethylamine, choline, arginine, leucine,lysine or N-methylglucamine).

The compounds of formula (I) have pharmcologically interestingproperties. These compounds have a strong affinity for cholecystokinin(CCK) and gastrin receptors and are thus useful in the treatment andprevention of disorders connected with CCK and gastrin at the level ofthe nervous system and the gastrointestinal system.

These compounds can thus be used for the treatment or prevention ofpsychoses, anxiety disorders, panic attacks, Parkinson's disease,tardive dyskinesia, irritable bowel syndrome, acute pancreatitis,ulcers, intestinal motility disorders, certain tumors sensitive to CCK,as an appetite regulator, in weaning from chronic treatments and alcoholor drug abuse and to control the constriction of the pupil of the eye.

These compounds also have a potentiating effect on the analgesicactivity of narcotic and non-narcotic medicaments. In addition, they canhave an analgesic effect of their own.

Among other things, the compounds having a strong affinity for CCKreceptors modify memorization capacities. As a consequence, thesecompounds can be efficacious in memory disorders.

The affinity of the compounds of formula (I) for CCK receptors has beendetermined according to a technique inspired by that of A. SAITO et al.,(J. Neuro. Chem., 37, 483-490 (1981) at the cerebral cortex level andthe pancreas level.

In these tests, the IC₅₀ of the compounds of formula (I) is generallyless than or equal to 1000 nM.

Amongst other things, it is known that the products which recognize thecentral CCK receptors have a similar specificity for the gastrinreceptors in the gastrointestinal tract (BOCK et al., J. Med. Chem., 32,16-23 (1989); REYFELD et al., Am. J. Physiol., 240, G255-266 (1981);BEINFELD et al., Neuropetides, 3, 411-427 (1983)).

The compounds of formula (I) have a low toxicity. Their LD₅₀ isgenerally greater than 40 mg/kg subcutaneously in the mouse.

Of particular interest are the compounds of formula (I) for which R₁represents a hydrogen atom, R₂ represents an alkyl radical or--CH(R₅)COR₆ in which R₅ represents a hydrogen atom and R₆ represents an--NR₇ R₈ radical in which R₇ and R₈, together with the nitrogen atom towhich they are attached, form a heterocycle and in particular a1-pyrrolidinyl or piperidino cyclic system optionally substituted by oneor more alkyl radicals, R₃ represents (a) a phenyl radical substitutedby one or more substituents chosen from amongst the radicals -alk-SO₃ H,-alk-PO₃ H₂, --CH═NOH, --CH═NO-alk-COOX, --S-alk-COOX, --SO-alk-COOX,--SO₂ -alk-COOX, --CH═CH--COOX, -alk-CO--NHOH, --C(═NOH)--COOX,-alk-N(OH)--CO-alk, -alk-SO₂ H, --CH═CH-SO₃ H, --C(COOX)═N--O--alk-COOX,tetrazolylalkyl, or a group of formula: ##STR9## or (b) a cyclic systemof formula: ##STR10## in which R₉ represents an ═NOX, ═NO-alk-COOX,═CH--COOX, -alk-COOX, -alk-SO₂ H or -alk-SO₃ H radical, R₁₀ representsan oxygen or sulphur atom or a methylene or alkylamino radical and R₁₁represents a methylene or ethylene radical and R₄ represents a phenylradical.

The following compounds are of particular interest:

(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinylcarbonylmethyl)-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid,

(RS)-3-[3-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl)ureido]phenylmethanesulphonicacid,

(RS)-3-{3-[1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzo[f]diazepin-3-yl]-3-phenyl-2(E)propenoicacid,

(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(3,3-dimethylpiperidino)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid,

(RS)-{3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid,

(E)-(RS)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl)-N'-(1-hydroxyimino-6-indanyl)urea,

(E)-(RS)-2-{3,4-dihydro-6-[3-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl)ureido]-4-2H-benzopyranylidene}aceticacid,

(E)-(RS)-3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}-2-phenylmethyleneaminooxyaceticacid,

(RS)-2-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}-2-(carboxymethyloxyimino)aceticacid,

(RS)-5-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}benzyl}-2,2-dimethyl-1,3-dioxane-4,6-dione,

(E)-(RS)-2-{3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}ethylenesulphonicacid,

(RS)-5-{3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}benzyl}tetrazole,

(E)-(RS)-3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}-alpha-hydroxyiminophenylaceticacid,

(RS)-{3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid,

(RS)-{4-{3-[2,3-dihydro-1-(3,3-dimethylpiperidino)carbonylmethyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid,

(E)-(RS)-3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(3,3-dimethylpiperidino)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}-2-propenoicacid,

(RS)-{4-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid,

potassium(RS)-1-{3-[3-(RS)-2,3-dihydro-2-oxo-5-phenyl-1-methyl-1H-1,4-benzo[f]diazepin-3-yl)ureido]phenyl}ethanesulphonate,

(+)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid,

(-)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid,

(RS)-{3-{3-[(RS)-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylsulphinyl}aceticacid,

(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylsulphonyl}aceticacid,

(RS)-2-{3-{3-[(RS)-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}propionicacid.

EXAMPLES

The following examples illustrate the invention without limiting it.

EXAMPLE 1

A solution of 1 g of tert-butyl(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)-carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetatein 4 cm³ of trifluoroacetic acid is stirred at a temperature near to 20°C. for 20 hours and then poured into 200 cm³ of iced water. The solid isseparated by filtration and rinsed with 20 cm³ of water and then 20 cm³of diisopropyl ether. After recrystallization in ethanol, 0.65 g of(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)-carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}-phenylthio}aceticacid melting at 168° C. is obtained.

tert-Butyl(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinylcarbonylmethyl)-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetatecan be obtained in the following manner: a solution of 2.6 g oftert-butyl (3-isocyanatophenylthio)acetate in 10 cm³ of tetrahydrofuranis added, at a temperature near to 20° C., to a solution of 3.2 g of(RS)-3-amino-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepinein 40 cm³ of tetrahydrofuran. The mixture is stirred for 70 hours at atemperature near to 20° C. and then concentrated to dryness underreduced pressure (2.7 kPa) at 40° C. The residue is dissolved in 30 cm³of dimethylformamide. The solution is poured into 200 cm³ of iced waterand the solid is filtered, dried and chromatographed on 200 cm³ ofsilica (eluent: ethyl acetate). The fractions containing the expectedproduct are combined and concentrated to dryness under reduced pressure(2.7 kPa). 3.9 g of tert-butyl(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetateare obtained in the form of an amorphous solid which is used as such inthe subsequent syntheses.

(RS)-3-Amino-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepinecan be obtained in the following manner: a solution of 5.1 g of2,3-dihydro-3-hydroxyimino-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepinein 50 cm³ of methanol is added to a suspension of 1 g of 5% ruthenium oncarbon in 35 cm³ of methanol. The mixture is stirred for 30 hours at atemperature near to 70° C. under a hydrogen atmosphere (500 kPa). Thecatalyst is separated by filtration and the filtrate is concentratedunder reduced pressure (2.7 kPa). The residue is dissolved in 100 cm³ ofdichloromethane and extracted with 3 times 50 cm³ of a normal aqueoussolution of hydrochloric acid. The aqueous phases are combined andbrought to a pH near to 9 by addition of sodium hydrogencarbonate andthen extracted with 3 times 100 cm³ of dichloromethane. The organicphases are combined, dried over magnesium sulphate, filtered andconcentrated under reduced pressure (2.7 kPa). 3.25 g of(RS)-3-amino-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepineare obtained in the form of a solid foam which is used as such in thesubsequent syntheses.

2,3-Dihydro-3-hydroxyimino-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepinecan be prepared in the following manner: 9 g of2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepineare added, at a temperature near to -20° C., to a solution of 7.27 g ofpotassium tert-butoxide in 50 cm³ of tert-butanol and 150 cm³ oftetrahydrofuran, in portions, in the course of 50 minutes. Thesuspension is stirred for 3 hours at a temperature below -20° C. andthen 9.8 cm³ of isopentyl nitrite are added. The suspension is againstirred for 1 hour at a temperature near to 0° C. and then 5 cm³ ofacetic acid and 10 cm³ of water are added. After returning to atemperature near to 20° C., the precipitate is filtered and washed withpentane. After recrystallization in ethanol, 3.17 g of2,3-dihydro-3-hydroxyimino-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepine are thus obtained, melting above 260° C.

2,3-Dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo [f]diazepine is obtained in the followingmanner: a suspension of 25 g of 2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepine, 20.5 g of 1-chloroacetylpyrrolidine, 14.6 g of potassiumcarbonate and 17.6 g of potassium iodide in 250 cm³ of dimethylformamideis stirred for 170 hours at a temperature near to 25° C. The reactionmixture is poured into 1500 cm³ of iced water. The aqueous phase isseparated from the insoluble matter and extracted with 3 times 300 cm³of ethyl acetate. The organic extracts are combined, washed with 200 cm³of a saturated aqueous solution of sodium chloride, dried over magnesiumsulphate, filtered and concentrated to dryness under reduced pressure(2.7 kPa) at a temperature near to 45° C. After crystallization in ethylacetate, 14.7 g of2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)-carbonylmethyl-1H-1,4-benzo[f]diazepine are obtained, melting at 190° C.

tert-Butyl (3-isocyanatophenylthio)acetate can be obtained in thefollowing manner: a solution of 2.9 g of tert-butyl(3-aminophenylthio)acetate in 25 cm³ of toluene is added dropwise, at atemperature near to -30° C., to a suspension of 0.24 g of carbon in 1.46cm³ of trichloromethyl chloroformate and 15 cm³ of toluene. The reactionmixture is stirred for 2 hours at a temperature near to 20° C. and thenfor 2 hours and 30 minutes at a temperature near to 110° C. The reactionmixture is then cooled to a temperature near to 20° C., degassed bybubbling nitrogen in, filtered and then concentrated to dryness underreduced pressure (2.7 kPa) at 50° C. 2.6 g of tert-butyl(3-isocyanatophenylthio)acetate are thus obtained in the form of an oilwhich is used as such in the subsequent syntheses.

tert-Butyl (3-aminophenylthio)acetate can be prepared in the followingmanner: a solution of 25 g of 3-aminothiophenol and 39 g of tert-butylbromoacetate in 400 cm³ of ethanol is stirred for 3 hours at atemperature near to 25° C. and then concentrated under reduced pressure(2.7 kPa). The residue is dissolved in 500 cm³ of ethyl acetate. Thesolution is washed successively with 3 times 75 cm³ of a normal aqueoussolution of sodium hydroxide and 3 times 75 cm³ of a saturated aqueoussolution of sodium chloride and is concentrated under reduced pressure(2.7 kPa). The residue is then purified by chromatography on 800 cm³ ofsilica (eluent: cyclohexane/ethyl acetate (90:10 and then 80:20 byvolume)). The fractions containing the expected products are combinedand concentrated under reduced pressure (2.7 kPa). 24 g of tert-butyl(3-aminophenylthio)acetate are obtained in the form of an oil which isused as such in the subsequent syntheses.

1-Chloroacetylpyrrolidine can be prepared according to the methoddescribed by A. J. SPEZIALE et al., J. Am. Chem. Soc., 78, 2556 (1956).

2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzo [f]diazepine can be prepared bythe method described by L. H. STERNBACH et al., J. Org. Chem., 27, 3788(1962).

EXAMPLE 2

A solution of 2.65 g of(RS)-3-amino-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepine in 50 cm³ of 1,2-dichloroethane is added at a temperaturenear to 25° C. to a solution of 1.8 g of N,N'-carbonyldiimidazole in 30cm³ of 1,2-dichloroethane. The reaction mixture is stirred for 3 hoursat a temperature near to 25° C. and then a solution of 4.3 g oftetrabutylammonium 3-aminophenylmethanesulphonate in 70 cm³ of1,2-dichloroethane is added. The reaction mixture is stirred at atemperature near to 80° C. for 18 hours and then cooled to a temperaturenear to 25° C. and diluted with 150 cm³ of dichloromethane, washed withtwo times 100 cm³ of water, dried over magnesium sulphate, filtered andconcentrated to dryness under reduced pressure (2.7 kPa) at 60° C. Afraction of 2.8 g of the residue is purified by chromatography on 60 cm³of silica contained in a column of diameter 2 cm (eluent:dichloromethane/methanol (97:3 by volume)). The residue is dissolved in50 cm³ of methanol and treated with 10 g of acidic resin (IR 120). Thesuspension is filtered and washed with 3 times 50 cm³ of methanol andthen the filtrate is concentrated under reduced pressure and the residueis triturated in 50 cm³ of diethyl ether, filtered and washed with twotimes 25 cm³ of diethyl ether. 0.9 g of(RS)-3-[3-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl)ureido]phenylmethanesulphonic acid melting at 230° C.is thus obtained.

Tetrabutylammonium 3-aminophenylmethanesulphonate can be prepared in thefollowing manner: 1 g of 5% of palladium on carbon is added to asolution of 41.4 g of tetrabutylammonium 3-nitrophenylmethanesulphonatein 300 cm³ of ethanol. The suspension is stirred for 2 hours at atemperature near to 20° C. under a hydrogen atmosphere (128 kPa). Thecatalyst is separated by filtration and the filtrate is concentrated todryness under reduced pressure (2.7 kPa) at 50° C. 42.2 g oftetrabutylammonium 3-aminophenylmethanesulphonate are thus obtained inthe form of an oil which is used as such in the subsequent syntheses.

Tetrabutylammonium 3-nitrophenylmethanesulphonate can be prepared in thefollowing manner: 6.9 g of sodium 3-nitrophenylmethanesulphonate andthen 9.9 g of tetrabutylammonium hydrogensulphate are added to 800 cm³of an aqueous solution of 0.5M potassium dihydrogenphosphate. Themixture is extracted with 500 cm³ of methylene chloride. The organicphase is dried over magnesium sulphate and concentrated to dryness underreduced pressure at 40° C. 13 g of tetrabutylammonium3-nitrophenylmethanesulphonate are thus obtained in the form of an oilwhich is used as such in the subsequent syntheses.

Sodium 3-nitrophenylmethanesulphonate can be prepared according to thetechnique described by PURGOTTI et al., Gazz. Chim. Ital., 30, II, 247.

(RS)-3-Amino-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepinecan be obtained according to the technique described by M.G. BOCK etal., J. Org. Chem., 52, 3232 (1987).

EXAMPLE 3

3.4 cm³ of a normal aqueous solution of sodium hydroxide are added to asuspension of 1.7 g of ethyl(E)-(RS)-3-{3-[1-(N-methyl-N-phenylcarbamoylmethyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzo[f]diazepin-3-yl]ureido}-3-phenyl-2-propenoatein 6 cm³ of ethanol and the mixture is brought to a temperature near to80° C. in the course of 30 minutes. After cooling to a temperature nearto 20° C., 20 cm³ of water are added and the mixture is then washed with50 cm³ of ethyl acetate. The aqueous phase is acidified to pH 1 with 4cm³ of a normal aqueous solution of hydrochloric acid. After extractionwith 50 cm³ of dichloromethane, the organic phase is dried overmagnesium sulphate and concentrated under reduced pressure (2.7 kPa).0.6 g of(RS)-3-{3-[1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzo[f]diazepin-3-yl]-3-phenyl-2(E)propanoicacid melting at 180° C. is obtained after recrystallization indiisopropyl ether.

Ethyl(E)-(RS)-3-{3-[1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzo[f]diazepin-3-yl]ureido}-3-phenyl-2-propenoate can be prepared in the following manner: a solution of 0.85 gof ethyl (E)-3-(3- isocyanatophenyl)-2-propenoate in 10 cm³ oftetrahydrofuran is added under an inert atmosphere at a temperature nearto 20° C. in the course of 15 minutes to a solution of 1.57 g of(RS)-2-(3-amino-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-1-yl)-N-methylacetanilidein 20 cm³ of tetrahydrofuran. The reaction mixture is stirred at atemperature near to 20° C. for 4 hours. After concentration to drynessunder reduced pressure (2.7 kPa) at 50° C., the residue is dissolved in10 cm³ of ethyl acetate and then diluted with 30 cm³ of diethyl ether.1.7 g of(E)-(RS)-3-{3-[1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzo[f]diazepin-3-yl]ureido}-3-phenyl-2-propenoatemelting at 238° C. are thus obtained.

Ethyl (E)-3-(3-isocyanatophenyl)-2-propenoate can be prepared in thefollowing manner: a suspension of 0.15 g of carbon in a solution of 1 gof bis(trichloromethyl) carbonate in 10 cm³ of toluene is cooled to atemperature near to -20° C. under an inert atmosphere. A solution of 1.2g of ethyl (E)-metaaminocinnamate in 10 cm³ of toluene is run in in thecourse of 15 minutes keeping the temperature at -20° C. The reactionmixture is stirred for 2 hours at a temperature near to 20° C. and thenfor 2 hours 30 minutes at a temperature near to 110° C. The reactionmixture is cooled to a temperature near to 20° C., the black matter isfiltered on Clarcel, rinsed with 20 cm³ of dichloromethane andconcentrated under reduced pressure (2.7 kPa) to obtain 1.35 g of ethyl(E)-3-(3-isocyanatophenyl)-2-propenoate in the form of an oil which isused as such in the subsequent syntheses.

(RS)-2-(3-Amino-2,3-dihydro-2-oxo-5phenyl-1H-1,4-benzo[f]diazepin-1-yl)-N-methylacetanilidecan be prepared in the following manner: a suspension of 10 g of Raneynickel in a solution of 5.3 g of2-(2,3-dihydro-3-hydroxyimino-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-1-yl)-N-methylacetanilidein 75 cm³ of methanol is stirred for 24 hours at a temperature near to20° C. under a hydrogen atmosphere (1.5 MPa). The catalyst is separatedby filtration and the filtrate is concentrated under reduced pressure(2.7 kPa) at 35° C. The residue is purified by chromatography on 400 cm³of silica contained in a column of diameter 4 cm (eluents:dichloromethane and then dichloromethane/methanol (98:2 and then 95:5 byvolume)). The fractions containing the expected product are combined andconcentrated under reduced pressure (2.7 kPa). 1 g of(RS)-2-(3-amino-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-1-yl)-N-methylacetanilidemelting at 80° C. is thus obtained.

2-(2,3-Dihydro-3-hydroxyimino-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-1-yl)-N-methylacetanilidecan be prepared in a manner analogous to that described in Example 1 forthe preparation of2,3-dihydro-3-hydroxyimino-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepinebut starting from 5.04 g of potassium tert-butoxide, 30 cm³ oftert-butanol, 130 cm³ of tetrahydrofuran, 6.5 g of2-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-1-yl)-N-methylacetanilideand 3.2 cm³ of isopentyl nitrite. 5.3 g of2-(2,3-dihydro-3-hydroxyimino-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-1-yl)-N-methylacetanilideare obtained in the form of a solid foam which is used as such in thesubsequent syntheses.

2-(2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-1-yl)-N-methylacetanilidecan be obtained in a manner analogous to that described in Example 1 forthe preparation of2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepine,but starting from 4.6 g of N-methyl-2-bromoacetanilide, 4.7 g of2,3-dihydro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepine, 3.5 gof potassium carbonate and 50 cm³ of dimethylformamide. 8 g of2-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-1-yl)-N-methylacetanilideare thus obtained which are used as such in the subsequent syntheses.

N-Methyl-2-bromoacetanilide can be prepared in the following manner:11.1 g of triethylamine and a solution of 20.4 g of bromoacetyl bromidein 10 cm³ of dichloromethane are added successively, at temperature nearto -5° C., to a solution of 10.7 g of N-methylaniline in 65 cm³ ofdichloromethane. The suspension is stirred for 2 hours at a temperaturenear to 20° and 25 cm³ of water are then added. The aqueous phase isseparated by decantation and reextracted with two times 15 cm³ ofdichloromethane. The organic phases are combined, washed with 3 times 25cm³ of water, dried over magnesium sulphate, filtered and thenconcentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 100cm³ of diethyl ether are added to the residual oil; the insolubleproduct is separated by filtration and washed with 3 times 15 cm³ ofdiethyl ether. The filtrates are combined and concentrated to drynessunder reduced pressure (2.7 kPa) at 40° C. 20.5 g ofN-methyl-2-bromoacetanilide are thus obtained in the form of an oilwhich is used as such in the subsequent syntheses.

Ethyl (E)-meta-aminocinnamate can be obtained by the method described inthe Patent Application NL 7,416,449 (C.A., 84, 58882q).

EXAMPLE 4

Working as in Example 1, but starting from 1.5 g of tert-butyl(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(3,3-dimethylpiperidino)carbonylmethyl-1H-1,4-benzo[f]-diazepin-3-yl]ureido}phenylthio}acetateand 5.5 cm³ of trifluoroacetic acid, 0.55 g of(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(3,3-dimethylpiperidino)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid melting at 240° C. is obtained.

tert-Butyl(RS)-{3-{3-[2,3-dihydro-2-oxo-phenyl-1-(3,3-dimethylpiperidino)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetatecan be prepared in a manner analogous to that described in Example 1 forthe preparation of tert-butyl(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetate,but starting from 1.65 g of(RS)-3-amino-2,3-dihydro-2-oxo-5-phenyl-1-(3,3-dimethylpiperidino)carbonylmethyl-1H-1,4-benzo[f]diazepineand 1.13 g of tert-butyl (3-isocyanatophenylthio)acetate in 35 cm³ oftetrahydrofuran. 1.57 g of tert-butyl(RS)-{3-{3-[2,3-dihydro-2-oxo-phenyl-1-(3,3-dimethylpiperidino)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}-phenylthio}acetatemelting at 110° C. are thus obtained.

(RS)-3-Amino-2,3-dihydro-2-oxo-5-phenyl-1-(3,3-dimethylpiperidino)carbonylmethyl-1H-1,4-benzo[f]diazepinecan be prepared in a manner analogous to that described in Example 1 forthe preparation of(RS)-3-amino-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepine,but starting from 7.1 g of2,3-dihydro-1-(3,3-dimethylpiperidino)carbonylmethyl-3-hydroxyimino-2-oxo-5-phenyl-1,4-benzo[f]diazepineand 1.8 g of 5% ruthenium on carbon in 160 cm³ of methanol. 4.95 g of(RS)-3-amino-2,3-dihydro-2-oxo-5-phenyl-1-(3,3-dimethylpiperidino)carbonylmethyl-1H-1,4-benzo[f]diazepinemelting at 88° C. are thus obtained.

2,3-Dihydro-1-(3,3-dimethylpiperidino)carbonylmethyl-3-hydroxyimino-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepinecan be obtained in a manner analogous to that described in Example 1 forthe preparation of2,3-dihydro-3-hydroxyimino-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepine,but starting from 16.5 g of2,3-dihydro-1-(3,3-dimethylpiperidino)carbonylmethyl-2-oxo-5-phenyl-1H1,4-benzo[f]diazepine,11.88 g of potassium tert-butoxide and 7 cm³ of isopentyl nitrite in 300cm³ of toluene. 7 g of2,3-Dihydro-1-(3,3-dimethylpiperidino)carbonylmethyl-3-hydroxyimino-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepinemelting at 145° C. are thus obtained.

2,3-Dihydro-1-(3,3-dimethylpiperidino)carbonylmethyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepinecan be prepared in the following manner: a solution of 31.9 g of(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-1-yl)acetic acid,17.6 g of N,N'-carbonyldiimidazole and 0.66 g ofN,N-4-dimethylaminopyridine in 250 cm³ of tetrahydrofuran is stirred for18 hours at a temperature near to 20° C. A solution of 12.3 g of3,3-dimethylpiperidine in 60 cm³ of tetrahydrofuran is then added andthe mixture is stirred again for 5 hours 30 minutes. The reactionmixture is poured into 500 cm³ of water. The aqueous phase is extractedwith 3 times 500 cm³ and then again with once 250 cm³ of diethyl ether.The organic extracts are combined, washed with 3 times 250 cm³ of water,dried over magnesium sulphate and concentrated to dryness under reducedpressure (2.7 kPa) at 40° C. The residue is purified by chromatographyon 700 cm³ of silica contained in a column of diameter 6 cm (eluents:dichloromethane and then dichloromethane/methanol (98:2 by volume). Thefractions containing the expected product are combined and concentratedto dryness under reduced pressure (2.7 kPa). After crystallisation inpentane, 15 g of2,3-dihydro-1-(3,3-dimethylpiperidino)carbonylmethyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepinemelting at 86° C. are thus obtained.

(2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-1-yl)acetic acid canbe prepared in a manner analogous to that described in Example 1 for thepreparation of(RS)-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylythio}aceticacid, but starting from 27.7 g of tert-butyl(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-1-yl)acetate and 100cm³ of trifluoroacetic acid. 21.9 g of(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-1-yl)acetic acidmelting at 163° C. are obtained.

tert-Butyl (2,3-dihydro-2-oxo-5-phenyl-1H-benzo[f]diazepin-1-yl)acetatecan be prepared in the following manner: 0.99 g of a dispersion of 60%sodium hydride in liquid paraffin is added at a temperature near to 0°C. to a solution of 0.7 g of2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepine in 5 cm³ oftetrahydrofuran. The reaction mixture is stirred for 2 hours at atemperature near to 0° C. and then a solution of 0.48 cm³ of tert-butylbromoacetate in 5 cm³ of tetrahydrofuran is added. The reaction mixtureis stirred for 2 hours at a temperature near to 17° C. and then 5 cm³ ofwater are added and the mixture is poured into 100 cm³ of water. Theaqueous phase is extracted with 4 times 75 cm³ of ethyl acetate. Theorganic extracts are combined, washed with 25 cm³ of a normal aqueoussolution of ammonium carbonate, dried over magnesium sulphate andbrought to dryness under reduced pressure (2.7 kPa) at 40° C. Aftercrystallization in pentane, 0.99 g of tert-butyl(2,3-dihydro-2-oxo-5-phenyl-1H-benzo[f]diazepin-1-yl)acetate melting at149° C. is thus obtained.

EXAMPLE 5

Working as in Example 1, but starting from 2 g of tert-butyl(RS)-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetateand 10 cm³ of trifluoroacetic acid and recrystallizing in 60 cm³ ofethanol, 1.42 g of (RS){3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid melting at 200° C. with decomposition are obtained.

tert-Butyl(RS)-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetatecan be obtained in the following manner: a solution of 3.1 g of(RS)-3-amino-1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepinein 25 cm³ of tetrahydrofuran is added in the course of 10 minutes at atemperature near to 20° C. to a solution of 2.38 g of tert-butyl(3-isocyanatophenylthio)acetate in 10 cm³ of tetrahydrofuran. Themixture is stirred for 18 hours at a temperature near to 20° C. anddiluted with 60 cm³ of diethyl ether. The precipitate is filtered. 3.6 gof tert-butyl(RS)-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetatemelting at 220° C. with decomposition are thus obtained.

(RS)-3-Amino-1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepinecan be obtained in the following manner: a suspension of 10.3 g of1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-3-hydroxyimino-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepineand 2 g of 5% ruthenium on carbon in 200 cm³ of methanol is stirred for15 hours at a temperature near to 70° C. under a hydrogen atmosphere(800 kPa). The catalyst is separated by filtration and the filtrate isconcentrated under reduced pressure (2.7 kPa). The residue is purifiedby chromatography on a column of diameter 6 cm containing 600 cm³ ofsilica, eluting at first with 400 cm³ of pure dichloromethane, then with3 liters of dichloromethane/ethanol mixture (95:5 by volume) and thendichloromethane/ethanol mixture (90:10 by volume). The fractions between1.25 and 5 liters are combined and concentrated under reduced pressure(2.7 kPa) to give 8.1 g of white solid foam. By taking up in diisopropylether, 7.6 g of(RS)-3-amino-1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepinemelting at 152° C. are obtained.

1-(N,N-Diethylcarbamoylmethyl)-2,3-dihydro-3-hydroxyimino-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepinecan be obtained in a manner analogous to that described in Example 1 forthe preparation of2,3-dihydro-3-hydroxyimino-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonyl-methyl-1H-1,4-benzo[f]diazepine, but starting from 11.8 g of1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepine,7.6 g of potassium tert-butoxide and 5 cm³ of isopentyl nitrite in 350cm³ of toluene. 10.42 g of1-(N,N-diethylcarbamoylmethyl-2,3-dihydro-3-hydroxyimino-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepinemelting at 220° C. are thus obtained.

1-(N,N-Diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepinecan be obtained in the following manner: 0.75 g of potassium iodide and17.5 g of potassium carbonate are added to a solution of 10 g of2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepine and 6.65 g ofN,N-diethyl-2-chloroacetamide in 100 cm³ of dimethylformamide. Thesuspension obtained is stirred at a temperature near to 20° C. for 16hours. The reaction mixture is concentrated under reduced pressure (1.2kPa). The residue is taken up in 100 cm³ of ethyl acetate. The organicphase is washed two times with water and then dried over magnesiumsulphate and concentrated to dryness under reduced pressure (2.7 kPa).The residue is purified by chromatography on a column of diameter 6 cmcontaining 900 cm³ of silica, eluting first with a cyclohexane/ethylacetate mixture (50:50 by volume) and then with pure ethyl acetate andcollecting fractions of 125 cm³. The fractions of between 3.75 and 4.75liters are combined and evaporated to dryness to give 11.9 g of1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepinein the form of a solid foam which is used as such in the subsequentsyntheses.

EXAMPLE 6

A solution of 2.5 g of(RS)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl)-N'-(1-oxo-6-indanyl)urea and 6.12 g of hydroxylamine hydrochloride in80 cm³ of aqueous pyridine (75:25 by volume) is heated for 2 minutes toa temperature near to 100° C. The reaction mixture is cooled to atemperature near to 20° C. and concentrated under reduced pressure (2.7kPa). It is diluted with 200 cm³ of water, acidified to pH 1 with anaqueous solution of 6N hydrochloric acid and extracted with 200 cm³ ofethyl acetate. The organic phase is washed with two times 200 cm³ ofwater, dried over magnesium sulphate, and then concentrated to dryness.The residue is purified by chromatography under pressure (4.1 MPa) on acolumn of 300 g of silica of 15-20 microns, eluting first with 3 litersof dichloromethane/methanol mixture (98:2 by volume), and then 850 cm³of dichloromethane/methanol mixture (95:5 by volume). The fractionsbetween 1750 and 3850 cm³ are combined and evaporated to dryness to give1.7 g of a white solid foam. After recrystallization in 30 cm³ of ethylacetate, 1 g of (E)-(RS)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl)-N'-(1-hydroxyimino-6-indanyl)urea melting at218° C. is obtained.

(RS)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl)-N'-(1-oxo-6-indanyl)urea can be obtained inthe following manner: a solution of 1.9 g of 6-isocyanato-1-indanone in20 cm³ of tetrahydrofuran is added in the course of 10 minutes to asolution of 2.5 g of3-amino-1-methyl-2-oxo-5-phenyl-1,4-benzo[f]diazepine in 90 cm³ oftetrahydrofuran. After stirring for 15 minutes at a temperature near to20° C., insoluble matter is filtered and washed with two times 15 cm³ oftetrahydrofuran and with two times 50 cm³ of diisopropyl ether, toobtain 3.2 g of(RS)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl)-N'-(1-oxo-6-indanyl)ureamelting at about 270° C. with decomposition.

6-Isocyanato-1-indanone can be prepared in the following manner: asolution of 1.6 g of bis(trichloromethyl) carbonate in 20 cm³ of tolueneis added in the course of 25 minutes to a suspension cooled to about-20° C. of 1.6 g of 6-amino-1-indanone and 0.2 g of animal charcoal in30 cm³ of toluene, at a temperature near to -20° C. The mixture isallowed to warm up to ambient temperature, then it is heated for 2 hoursat a temperature near to 110° C. The suspension obtained is cooled to atemperature near to 20° C. and filtered, and the filtrate isconcentrated under reduced pressure (2.7 kPa) to give 1.9 g of6-isocyan-ato -1-indanone melting at 72° C.

6-Amino-1-indanone can be prepared according to the method described byC. K. INGOLD and H. A. PIGGOT, J. Chem. Soc., 123, 1469 (1923).

EXAMPLE 7

70 cm³ of an aqueous solution of 0.1N sodium hydroxide are added to asolution of 1.9 g of ethyl(E)-(RS)-2-{3,4-dihydro-6-[3-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl)ureido]-4-2H-benzopyranylidene}acetatein 40 cm³ of pyridine, and the mixture is then heated to a temperaturenear to 100° C. for 2 hours. After cooling to a temperature near to 20°C., the mixture is concentrated under reduced pressure (1.2 kPa). Theresidue is diluted with 100 cm³ of water and washed with 100 cm³ ofdimethyl ether. The aqueous phase is brought to pH 1 with an aqueoussolution of 4N hydrochloric acid and extracted with 100 cm³ of ethylacetate. The organic phase is washed with 200 cm³ of water, dried overmagnesium sulphate and concentrated to dryness. The residue obtained ispurified by chromatography on a column of diameter 2.5 cm containing 160cm³ of silica, eluting with 500 cm³ of dichloromethane, and then 2liters of dichloromethane/methanol mixture (98:2 by volume) then 1 literof dichloromethane/methanol mixture (95:5 by volume), and then 2 litersof dichloromethane/methanol mixture (93:7 by volume) and collectingfractions of 250 cm³. The fractions between 1 and 5.5 liters arecombined and evaporated to dryness to give 0.33 g of a yellow solid. Byrecrystallization in 25 cm³ of diisopropyl ether, 0.26 g of(E)-(RS)-2-{3,4-dihydro-6-[3-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl)ureido]-4-2H-benzopyranylidene}aceticacid melting at 250° C. is obtained.

Ethyl(E)-(RS)-2-{3,4-dihydro-6-[3-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl)ureido]-4-2H-benzopyranylidene}acetatecan be prepared in the following manner: a solution of 2.1 g of ethyl(E)-2-(3,4-dihydro-6-isocyanato-4-2H-benzopyranylidene)acetate in 20 cm³of tetrahydrofuran is added in the course of 10 minutes to a solution of2 g of (RS)-3-amino-1-methyl-2-oxo-5-phenyl-1,4-benzo[f]diazepine in 25cm³ of tetrahydrofuran. After stirring for 1 hour at a temperature nearto 20° C., the reaction mixture is concentrated under reduced pressure(2.7 kPa) and taken up in 50 cm³ of ethyl acetate. The organic phase iswashed with 50 cm³ of water, dried over magnesium sulphate and thenevaporated to dryness to give 3.4 g of product in the form of an ochresolid foam. By crystallization in 40 cm³ of ethyl acetate, 2.4 g ofethyl(E)-(RS)-2-{3,4-dihydro-6-[3-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl)ureido]-4-2H-benzopyranylidene}acetatemelting at 230° C. are obtained.

Ethyl (E)-2-(3,4-dihydro-6-isocyanato-4-2H-benzopyranylidene)acetate canbe obtained in the following manner: a solution of 1.52 g ofbis(trichloromethyl) carbonate in 20 cm³ of toluene is added in thecourse of 10 minutes to a suspension of 2.4 g of ethyl(E)-2-(6-amino-3,4-dihydro-4-2H-benzopyranylidene)acetate and 0.1 g ofanimal charcoal in 45 cm³ of toluene, cooled to a temperature near to-20° C. After stirring for 10 minutes at a temperature near to -20° C.,the mixture is brought for 1 hour to a temperature near to 110° C.before cooling to a temperature near to 20° C. It is filtered on Celiteand the filtrate is concentrated to dryness under reduced pressure (2.7kPa) to obtain 2.7 g of(E)-2-(3,4-dihydro-6-isocyanato-4-2H-benzopyranylidene)acetate in theform of an oil which is used as such in the subsequent syntheses.

Ethyl (E)-2-(6-amino-3,4-dihydro-4-2H-benzopyranylidene)acetate can beprepared in the following manner: 2.7 cm³ of a 12N aqueous solution ofhydrochloric acid are added to a suspension of 3.4 g of ethyl(E)-2-(6-nitro-3,4-dihydro-4-2H-benzopyranylidene)acetate and 2.7 g ofiron powder in 90 cm³ of 50% aqueous ethanol. The mixture is heated to atemperature near to 80° C. for 1 hour and then cooled to a temperaturenear to 50° C. The mixture is filtered on Celite and washed with 20 cm³of ethanol and then 20 cm³ of water and then evaporated under reducedpressure (2.7 kPa). The residue is acidified to pH 1 with 25 cm³ of an Nsolution of hydrochloric acid and washed with 100 cm³ of diethyl ether.The aqueous phase is rendered alkaline to pH 8 with sodiumhydrogencarbonate and extracted with 200 cm³ of ethyl acetate. Theextract is dried over magnesium sulphate and the filtrate is evaporatedto obtain 2.5 g of ethyl(E)-2-(6-amino-3,4-dihydro-4-2H-benzopyranylidene)acetate melting at 97°C.

Ethyl (E)-2-(6-nitro-3,4-dihydro-4-2H-benzopyranylidene)acetate can beobtained in the following manner: 9.9 g of a 60% suspension of sodiumhydride in oil are introduced into an apparatus purged with nitrogen.The oil is removed by two washings with 100 cm³ of hexane. 200 cm³ oftetrahydrofuran are added and then, at a temperature near to 20° C., 62cm³ of triethyl phosphonoacetate are run in in the course of 30 minutes.After stirring for 10 minutes at a temperature near to 20° C., 12 g of3,4-dihydro-6-nitro-4-one 2H-benzopyran are run in. After stirring for 1hour at room temperature near to 20° C., the reaction mixture isconcentrated under reduced pressure (2.7 kPa), diluted with 500 cm³ ofwater and extracted with two times 200 cm³ of ethyl acetate. The organicphases are combined and washed with 500 cm³ of water, dried overmagnesium sulphate and evaporated to dryness to give an oil which ischromatographed on a column of diameter 6 cm containing 800 cm³ ofsilica, eluting with a cyclohexane/ethyl acetate mixture (93:7 byvolume) and collecting fractions of 200 cm³. The fractions between 1 and2.2 liters are collected and evaporated to dryness to give 3.5 g ofethyl (E)-2-(6-nitro-3,4-dihydro-4-2H-benzopyranylidene)acetate meltingat 135° C.

3,4-Dihydro-6-nitro-4-2H-benzopyranone can be obtained by the methoddescribed by C. D. HURD and S. HAYAO, J. Amer. Chem. Soc., 76, 5065(1954).

EXAMPLE 8

A solution of 3.5 g of tert-butyl(E)-(RS)-3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}-2-phenylmethyleneaminooxyacetatein 15 cm³ of trifluoroacetic acid is stirred for 2 hours at atemperature near to 20° C. The reaction mixture is concentrated underreduced pressure (2.7 kPa). The residue is taken up in 50 cm³ of waterand the solution is extracted with 50 cm³ of ethyl acetate. The organicphase is dried over magnesium sulphate and evaporated to dryness toobtain 3 g of yellow oil. By crystallisation in 40 cm³ of isopropylacetate, 1.6 g of(E)-(RS)-3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}-2-phenylmethyleneaminooxyaceticacid melting at 175° C. are obtained.

tert-Butyl(E)-(RS)-3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}-2-phenylmethyleneaminooxyacetatecan be obtained in the following manner: a solution of 2.35 g oftert-butyl (E)-3-isocyanatophenylmethyleneaminooxyacetate in 25 cm³ oftetrahydrofuran is added in the course of 10 minutes to a solution of2.8 g of(RS)-3-amino-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepinein 30 cm³ of tetrahydrofuran and kept for 1 hour at a temperature nearto 20° C. The reaction mixture is evaporated to dryness under reducedpressure (2.7 kPa). The residue is purified by chromatography on acolumn of diameter 4 cm containing 400 cm³ of silica, eluting first with500 cm³ of ethyl acetate/cyclohexane mixture (40:60 by volume) and thenwith 500 cm³ of ethyl acetate/cyclohexane mixture (50:50) by volume) andthen with 1 liters of ethyl acetate/cyclohexane mixture (60:40 byvolume) and then with 500 cm³ of ethyl acetate/cyclohexane mixture(80:20 by volume) and then with pure ethyl acetate and collectingfractions of 200 cm³. The fractions between 2.2 and 3 liters arecombined and evaporated to dryness to give 3.5 g of tert-butyl(E)-(RS)-3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}-2-phenylmethyleneaminooxyacetatein the form of a solid foam which is used as such in the subsequentsyntheses.

tert-Butyl (E)-3-isocyanatophenyl-methyleneaminooxyacetate can beobtained in the following manner: 0.6 g of animal charcoal is added to asolution of 6.2 g of tert-butyl (E)-3-phenylmethyleaminooxy acetate in100 cm³ of toluene, this suspension is cooled to a temperature near to-30° C., and then 3 cm³ of trichloromethyl chloroformate in 5 cm³ oftoluene are added in the course of 10 minutes and the mixture is allowedto warm to a temperature near to 20° C. before heating for 2 hours at atemperature near to 110° C. The mixture is cooled to a temperature nearto 20° C. and filtered on Celite. The precipitate is washed with 25 cm³of toluene and the toluene phases are combined and concentrated todryness (2.7 kPa). 6.8 g of tert-butyl(E)-3-isocyanatophenylmethyleneaminooxyacetate are thus obtained in theform of an oil which is used as such in the subsequent syntheses.

tert-Butyl (E)-3-aminophenylmethyleneaminooxyacetate can be obtained inthe following manner: 0.75 of platinum dioxide is added to a solution of7.5 g of tert-butyl (E)-3-phenylmethyleneaminooxyacetate in 100 cm³ ofethanol. The suspension is stirred for 45 minutes at a temperature nearto 20° C. under a hydrogen atmosphere (128 kPa). The catalyst isseparated by filtration and the filtrate is concentrated under reducedpressure (2.7 kPa). The residue is taken up in 50 cm³ of water andextracted with 50 cm³ of ethyl acetate. After drying over magnesiumsulphate, the filtrate is evaporated to dryness to obtain 6.2 g oftert-butyl (E)-3-aminophenylmethyleneaminooxyacetate in the form of anoil which is used as such in the subsequent syntheses.

tert-Butyl (E)-3-phenylmethyleneaminooxyacetate can be obtained in thefollowing manner: working under an argon atmosphere, 1.3 g of a 60%dispersion of sodium hydride in oil are washed with two times 50 cm³ ofhexane. 100 cm³ of tetrahydrofuran are added and then the mixture iscooled to a temperature near to 5° C. A solution of 4.98 g of(E)-3-nitrobenzaldoxime in 20 cm³ of tetrahydrofuran is added in thecourse of 15 minutes and the mixture is stirred for 1 hour at atemperature near to 20° C. 5 cm³ of tert-butyl 2-bromoacetate are thenrun in in the course of 15 minutes and the mixture is stirred at atemperature near to 25° C. 200 cm³ of water and 100 cm³ of ethyl acetateare run in. The organic phase is decanted and washed with 100 cm³ ofwater. The organic phases are dried over magnesium sulphate and thefiltrate is concentrated to dryness (2.7 kPa) to obtain tert-butyl(E)-3-nitrophenylmethyleneaminooxyacetate melting at 110° C.

(E)-3-Nitrobenzaldoxime can be prepared by the method described by S.GABRIEL, Ber., 16, 1997 (1883).

EXAMPLE 9

A suspension of 1.3 g of a mixture of Z and E isomers (50:50) of(RS)-{1-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}-1-ethoxycarbonylmethylene}-2-aminooxyaceticacid in 15 cm³ of ethanol, 3.8 cm³ of 1N sodium hydroxide and 5 cm³ ofwater is stirred for 16 hours at a temperature near to 20° C. Thereaction mixture is concentrated under reduced pressure (2.7 kPa) anddiluted with 50 cm³ of water. The aqueous phase is washed with 30 cm³ ofdiethyl ether and then acidified to pH 1 with 5 cm³ of a 1N aqueoussolution of hydrochloric acid. The aqueous phase is extracted with 50cm³ of ethyl acetate, dried over magnesium sulphate and concentratedunder reduced pressure to a volume of 10 cm³ before diluting with 40 cm³of diisopropyl ether. By filtration, 0.63 g of a mixture of Z and Eisomers (50:50) of(RS)-2-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}-2-(carboxymethyloxyimino)aceticacid melting at 190° C. is obtained.

The mixture of Z and E isomers (50:50) of(RS)-{1-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}-1-ethoxycarbonylmethylene}-2-aminooxyaceticacid can be obtained in the following manner: a solution of 1.45 g of amixture of Z and E isomers (50:50) of ethyl(RS)-2-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}-2-(tert-butoxycarbonylmethoxyimino)acetatein 30 cm³ of trifluoroacetic acid is stirred for 2 hours at atemperature near to 20° C. The reaction mixture is concentrated underreduced pressure (2.7 kPa). The residue is taken up in 50 cm³ ofdiisopropyl ether to give 1.35 g of a white solid. This solid isdissolved in the presence of 1 g of sodium hydrogencarbonate in 50 cm³of water and the organic phase is rapidly washed with 50 cm³ of ethylacetate. The aqueous phase is acidified to pH=1 with a 1N aqueoussolution of hydrochloric acid. By extraction with 100 cm³ of ethylacetate, drying over magnesium sulphate and concentration to dryness,1.3 g of a mixture of Z and E isomers (50:50) of (RS)-{1-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}-1-ethoxycarbonylmethylene}-2-aminooxyaceticacid melting at about 150° C. are obtained.

The mixture of Z and E isomers (50:50) of ethyl(RS)-2-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}-2-(tert-butoxycarbonylmethoxyimino)acetatecan be obtained in the following manner: 1.55 g of a mixture of Z and Eisomers of ethyl3-isocyanato-alpha-tert-butoxycarbonylmethoxyiminophenylacetate in 10cm³ of tetrahydrofuran are added in the course of 5 minutes to asolution of 1.45 g of3-amino-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepinein 20 cm³ of tetrahydrofuran and the mixture is stirred for 3 hours at atemperature near to 20° C. The mixture is poured onto 50 cm³ of waterand extracted with 100 cm³ of ethyl acetate. The extract is dried overmagnesium sulphate and concentrated under reduced pressure (2.7 kPa).The residue (2.2 g) is purified by chromatography on a column ofdiameter 3.5 cm containing 200 cm³ of silica, eluting with adichloromethane/methanol mixture (97:3 by volume) and collectingfractions of 50 cm³. The fractions between 250 and 400 cm³ are combinedand evaporated to dryness to give 1.45 g of a mixture of Z and E isomers(50:50) of ethyl(RS)-2-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}-2-(tert-butoxycarbonylmethoxyimino)acetatein the form of a solid foam which is used as such in the subsequentsyntheses.

The mixture of Z and E isomers of ethyl3-isocyanato-alpha-tert-butoxycarbonylmethoxyiminophenylacetate can beobtained in the following manner: a solution of 0.67 g ofbis(trichloromethyl) carbonate in 15 cm³ of dry toluene is added in thecourse of 10 minutes to a suspension of 1.4 g of ethyl(Z)-3-amino-alpha-tert-butoxycarbonylmethoxyiminophenylacetate and 0.05g of animal charcoal in 30 cm³ of dry toluene cooled to a temperaturenear to -20° C. The mixture is allowed to warm to a temperature near to20° C. and is then brought for 1 hour to a temperature near to 110° C.The mixture is cooled to a temperature near to 20° C. and filtered onCelite, and the filtrate is washed with 5 cm³ of dry toluene andconcentrated to dryness under reduced pressure (1.2 kPa) to obtain 1.55g of a mixture of Z and E isomers of ethyl3-isocyanato-alpha-tert-butoxycarbonylmethoxyiminophenylacetate in theform of an oil which is used as such in the subsequent syntheses.

Ethyl (Z)-3-amino-alpha-tert-butoxycarbonylmethoxyiminophenylacetate canbe obtained in the following manner: 0.15 g of platinum dioxide is addedto a solution of 2.61 g of ethyl(Z)-3-nitro-alpha-tert-butoxycarbonylmethoxyiminophenylacetate in 70 cm³of ethanol. The suspension is stirred for 40 minutes at a temperaturenear to 20° C. under a hydrogen atmosphere (128 kPa). The catalyst isseparated by filtration and the filtrate is concentrated to drynessunder reduced pressure (2.7 kPa) to give 2.3 g of ethyl(Z)-3-amino-alpha-tert-butoxycarbonylmethoxyiminophenylacetate in theform of an oil which is used as such in the subsequent syntheses.

Ethyl (Z)-3-nitro-alpha-tert-butoxycarbonylmethoxy-iminophenylacetatecan be obtained in the following manner: 0.46 g of a 60% dispersion ofsodium hydride in oil is introduced into an apparatus purged with argon.The oil is removed by two washings with 40 cm³ of heptane. 30 cm³ oftetrahydrofuran are added, and then 2.5 g of ethyl(Z)-3-nitro-alpha-hydroxyiminophenylacetate in the course of 15 minutesat a temperature near to 20° C. After 10 minutes, 1.8 cm³ of tert-butyl2-bromoacetate in 10 cm³ of tetrahydrofuran are added in the course of10 minutes. After stirring for 1 hour at a temperature near to 20° C.,the mixture is diluted with 100 cm³ of ethyl acetate and washed with 100and then 50 cm³ of water, dried over magnesium sulphate, filtered andconcentrated to dryness under reduced pressure (2.7 kpa) to obtain 3 gof ethyl (Z)-3-nitro-alpha-tert-butoxycarbonylmethoxyiminophenylacetatein the form of an oil which is used as such in the subsequent syntheses.

Ethyl (Z)-3-nitro-alpha-hydroxyiminophenylacetate can be obtained in thefollowing manner: a solution of 62 g of hydroxylamine hydrochloride in200 cm³ of water is added to a solution of 10 g of ethyl3-nitrophenyl-glyoxylate in 250 cm³ of pyridine and the mixture isbrought for 2 hours to a temperature near to 100° C. The reactionmixture is concentrated under reduced pressure (1.2 kPa). The residue isdiluted with 250 cm³ of water and extracted with 250 cm³ of ethylacetate. The organic phase is washed with a 1N aqeuous solution ofhydrochloric acid, dried over magnesium sulphate, filtered andevaporated to dryness to give a white solid. This solid is purified bychromatography on a column of diameter 4 cm containing 500 cm³ ofsilica, eluting with a cyclohexane/ethyl acetate mixture and collectingfractions of 100 cm³. The fractions between 1 and 1.2 liters arecombined and concentrated to dryness to give 1.8 g of ethyl(E)-3-nitro-alpha-hydroxyiminophenylacetate in the form of a colorlessoil; the fractions between 1.4 and 1.6 liters are combined andconcentrated to dryness to give 2.5 g of ethyl(Z)-3-nitro-alpha-hydroxyiminophenylacetate in the form of a solid whichis used as such in the subsequent syntheses.

Ethyl 3-nitrophenylglyoxylate can be prepared by the method described byE. ADLEROVA, P. VEJDELKOVA and M. PROTIVA, Collection Czech. Chem.Commun., 29, 97-120 (1964).

EXAMPLE 10

A solution of 2 g of(RS)-2,3-dihydro-3-isocyanato-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepinein 15 cm³ of dry tetrahydrofuran is added in the course of 10 minutes toa solution of 1.1 g of5-(3-aminobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione in 20 cm³ of drytetrahydrofuran. After stirring for 1 hour at a temperature near to 20°C., 100 cm³ of ethyl acetate are run in and the organic phase isextracted with 50 cm³ of water and then 35 cm³ of a 5% aqueous solutionof sodium hydrogencarbonate. The aqueous phases are combined andacidified to pH 1 with a 2N aqueous solution of hydrochloric acid andthen extracted with 100 cm³ of ethyl acetate. The organic phase is driedover magnesium sulphate, filtered and evaporated to dryness underreduced pressure (2.7 kPa). The residue is purified by chromatographyunder pressure (4.1 MPa) on a column containing 300 g of 55-105 micronsilica, eluting with a dichloromethane/methanol mixture (97:3) byvolume. The fractions between 1850 and 2500 cm³ are combined andevaporated to dryness (2.7 kPa) to give 1.3 g of a residue which istaken up in 30 cm³ of diethyl ether. 1 g of(RS)-5-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}benzyl}-2,2-dimethyl-1,3-dioxane-4,6-dionemelting at 190° C. is thus obtained.

(RS)-2,3-Dihydro-3-isocyanato-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepinecan be obtained in the following manner: a solution of 0.82 g of bis(trichloromethyl) carbonate in 15 cm³ of toluene is added in the courseof 15 minutes to a suspension of 2 g of(RS)-3-amino-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepineand 0.03 g of animal charcoal in 30 cm³ of dry toluene cooled to atemperature near to -30° C. After stirring for 15 minutes at atemperature near to -30° C., the mixture is allowed to return to atemperature near to 20° C. and then brought to a temperature near to110° C. for 40 minutes. After cooling to a temperature near to 20° C.,the mixture is filtered on Celite, rinsed with 5 cm³ of dry toluene andconcentrated under reduced pressure (1.2 kPa) to obtain 2.1 g of(RS)-2,3-dihydro-3-isocyanato-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepinein the form of a solid foam which is used as such in the subsequentsyntheses.

5-(3-Aminobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione can be obtained inthe following manner: a suspension of 7 g of5-(3-nitrobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione and 0.2 g of10% palladium on carbon in 300 cm³ of ethanol is stirred for 40 minutesat a temperature near to 20° C. under a hydrogen atmosphere (128 kPa).The catalyst is separated by filtration and the filtrate is concentratedto dryness under reduced pressure (2.7 kPa) to give 6.4 g of residue.This residue is purified by chromatography on a column of diameter 4 cmcontaining 200 cm² of silica, eluting with an ethyl acetate/cyclohexanemixture (60:40 by volume) and collecting fractions of 60 cm³. Thefractions between 180 and 360 cm³ are combined and concentrated todryness to give 3.2 g of an oil which is again purified bychromatography under pressure (2.1 MPa) on a column containing 300 g of55-105 micron silica, eluting with a cyclohexane/ethyl acetate mixture(60:40 by volume). The fractions between 1850 and 2550 cm³ are combinedand evaporated to dryness (2.7 kPa) to give 1.3 g of5-(3-aminobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione in the form of anoil which is used as such in the subsequent syntheses.

5-(3-Nitrobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione can beobtained in the following manner: a solution of 30.2 g of3-nitrobenzaldehyde and 2,2-dimethyl-1,3-dioxane-4,6-dione in 400 cm³ ofdimethylformamide is stirred for 18 hours at a temperature near to 20°C. The reaction mixture is diluted with 500 cm³ of ethyl acetate, washedfive times with water, dried over magnesium sulphate, filtered andconcentrated to dryness (1.2 kPa) to give an oil. This oil iscrystallized in 100 cm³ of ethanol to give 26 g of5-(3-nitrobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione in the form ofa solid melting at 128° C.

EXAMPLE 11

A solution of 1.3 g of tetrabutylammonium(E)-2-(3-aminophenyl)ethylenesulphonate in 30 cm³ of dichloromethane isadded in the course of 5 minutes to a solution of(RS)-1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-3-isocyanato-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepineand 0.05 g of N,N-4-dimethylaminopyridine for 18 hours at a temperaturenear to 20° C., the mixture is heated for 2 hours 30 minutes to atemperature near to 60° C. The reaction mixture is concentrated underreduced pressure (2.7 kPa). The residue is chromatographed on a columnof diameter 3 cm containing 200 cm³ of silica eluting with adichloromethane/ethanol mixture (100:0, then 95:5, then 90:10, then80:20 by volume). The fractions containing the expected product arecombined and evaporated to dryness under reduced pressure to give 1.37 gof tetrabutylammonium(E)-(RS)-2-{3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}ethylenesulphonatein the form of a brown solid foam. This tetrabutylammonium salt isstirred in the presence of 10 g of sulphonic acid resin (IRN-77) in 50cm³ of methanol, for 16 hours, at a temperature near to 20° C. The resinis filtered and washed with three times 20 cm³ of methanol. The filtrateis stirred in the presence of 0.25 of animal charcoal, filtered andevaporated to dryness under reduced pressure (2.7 kPa). The residue isdissolved in 5 cm³ of methanol, diluted with 40 cm³ of ethanol and thencooled for 16 hours at a temperature of +5° C. 0.22 g of a solid is thusremoved. The filtrate is diluted with 50 cm³ of ethyl ether to obtain0.31 g of(E)-(RS)-2-{3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}ethylenesulphonicacid melting at 250° C. with decomposition.

(RS)-1-(N,N-Diethylcarbamoylmethyl)-2,3-dihydro-3-isocyanato-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepinecan be obtained as in Example 10 for the preparation of(RS)-2,3-dihydro-3-isocyanato-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepine,but starting from 1.6 g of(RS)-1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepine,0.89 g of bis(trichloromethyl)-carbamate and 0.1 g of animal charcoal in25 cm³ of toluene. 1.71 g of(RS)-1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-3-isocyanato-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepinecan thus be obtained in the form of a solid foam which is used as suchin the subsequent syntheses.

Tetrabutylammonium (E)-2-(3-aminophenyl)ethylenesulphonate can beobtained in the following manner: a solution of tetrabutylammonium(E)-2-(3-nitrophenyl)ethylenesulphonate in 30 cm³ of water and 30 cm³ ofa 20% solution of ammonium sulphide is stirred for 21 hours at atemperature near to 20° C., then heated for 2 hours 30 minutes at atemperature near to 60° C. and then heated for 3.5 hours at atemperature near to 80° C. The reaction mixture is concentrated todryness under reduced pressure (1.2 kPa) and the residue is taken up in60 cm³ of water, filtered and washed with two times 20 cm³ of water toeliminate an insoluble brown material. The filtrate is extracted with 7times 100 cm³ of dichloromethane. 10 g of sodium dihydrogenphosphate isadded, and the mixture is then reextracted with 3 times 100 cm³ ofdichloromethane. The chloromethylene phases are combined, dried overmagnesium sulphate and concentrated to dryness to give 4.48 g oftetrabutylammonium (E)-2-(3-aminophenyl)-ethylenesulphonate in the formof an oil which is used as such in the subsequent syntheses.

Tetrabutylammonium (E)-2-(3-nitrophenyl)ethylenesulphonate can beobtained in the following manner: a suspension of 13.08 g of ethyl(E)-2-(3-nitrophenyl)ethylenesulphonate in 25 cm³ of 95% sulphuric acidand 4 cm³ of water is brought in the course of 5.5 hours to atemperature near to 60° C. The reaction mixture is cooled to atemperature near to 20° C., poured onto 225 cm³ of water and washed with100 cm³ of diethyl ether. The organic phase is washed with 50 cm³ ofwater. The aqueous phases are treated with 16.35 g of tetrabutylammoniumhydrogensulphate and extracted with 200 cm³ and then twice with 100 cm³of dichloromethane. The organic phase is dried over magnesium sulphate,filtered and evaporated to give 22.6 g of tetrabutylammonium(E)-2-(3-nitrophenyl)ethylenesulphonate in the form of an oil which isused as such in the subsequent syntheses.

Ethyl (E)-2-(3-nitrophenyl)ethylenesulphonate can be prepared accordingto the method described by J. C. CARRETERO, M. DEMILLEQUAND, L. GHOSEZ,Tetrahedron, 43, (21), 5125-34 (1987).

EXAMPLE 12

The reaction is carried out as in Example 11, but starting from 3.2 g of(R,S)-1-(N,N-diethylcarbamoyl-methyl)-2,3-dihydro-3-isocyanato-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepineand 1.2 g of 5-(3-aminobenzyl)-tetrazole in 50 cm³ of tetrahydrofuran.After treatment, 0.4 g of(RS)-5-{3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}benzyl}tetrazolemelting at 110° C. is obtained.

5-(3-Aminobenzyl)tetrazole can be obtained according to the methoddescribed in the Patent WO 91/13907.

EXAMPLE 13

The reaction is carried out as in Example 3, but starting from 1 g ofmethyl(E)-(RS)-3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}-alpha-hydroxyiminophenylacetate and 4.1 cm³ of1N sodium hydroxide in a mixture of 10 cm³ of ethanol and 4 cm³ ofwater. After treatment, 0.7 g of (E)-(RS)-3-{3-[1-(N,Ndiethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}-alpha-hydroxyiminophenylacetic acid is obtainedin the form of a solid melting at 230° C.

Methyl (E)-(RS)-3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}-alpha-hydroxyiminophenylacetate can be obtainedin the following manner: the reaction is carried out as in Example 12,but starting from 3.5 g of(RS)-1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-3-isocyanato-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepine and 1.5 g of methyl(E)-3-amino-alpha-hydroxyiminophenylacetate in 30 cm³ oftetrahydrofuran. After treatment, 2.9 g of methyl(E)-(RS)-3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}-alpha-hydroxyiminophenylacetate are obtained inthe form of a solid which is used as such in the subsequent syntheses.

Methyl (E)-3-amino-alpha-hydroxyiminophenylacetate can be obtained inthe following manner: the reaction is carried out as in Example 9 forthe preparation of ethyl(Z)-3-amino-alpha-tert-butoxycarbonylmethoxyimino-phenylacetate, butstarting from 3.4 g of methyl(E)-3-nitro-alpha-hydroxyiminophenylacetate and 0.034 g of platinumdioxide in 20 cm³ of methanol. After treatment, 2.9 g of methyl(E)-3-amino-alpha-hydroxyiminophenylacetate are obtained in the form ofa solid which is used as such in the subsequent syntheses.

Methyl (E)-3-nitro-alpha-hydroxyiminophenylacetate can be obtained as inExample 9 for the preparation of ethyl(E)-3-nitro-alpha-hydroxyiminophenylacetate, but starting from 15 g ofmethyl 3-nitrophenylglyoxylate and 10 g of hydroxylamine hydrochloridein a mixture of 250 cm³ of pyridine and 30 cm³ of water, for 30 minutesat 70° C. After treatment, 3.4 g of methyl(E)-3-nitro-alpha-hydroxyiminophenylacetate melting at 140° C. and 6.1 gof methyl (Z)-3-nitro-alpha-hydroxyiminophenylacetate melting at 190° C.are obtained.

Methyl 3-nitrophenylglyoxylate can be prepared according to the methoddescribed by E. ADLEROVA, P. VEJDELKOVA, M. PROTIVA, Collection Czech.Chem. Commun., 29, 97-120 (1964).

EXAMPLE 14

The reaction is carried out as in Example 5, but starting from 0.6 g oftert-butyl(RS)-{3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4benzo[f]diazepin-3-yl]ureido}phenylthio}acetate and 10 cm³ of trifluoroaceticacid. After treatment, 0.39 g of(RS)-{3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetic acid melting at 194° C. isobtained.

tert-Butyl(RS)-{3-{3-[1-(N,N-diethylcarbamoyl-methyl)-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetate can be obtained as in Example5 for the preparation of tert-butyl(RS)-{3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetate, but starting from 0.53 g oftert-butyl (3-isocyanatophenylthio)acetate and 0.7 g of(RS)-1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzo[f]diazepine in 25 cm³ of tetrahydrofuran. After treatment, 0.6 g oftert-butyl(RS)-{3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetate is obtained in the form of asolid foam which is used as such in the subsequent syntheses.

(RS)-3-Amino-1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzo[f]diazepine can be obtained as in Example 5 for the preparation of(RS)-3-amino-1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]-diazepine, but starting from 2.5 g of1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-5-(2-fluorophenyl)-3-hydroxyimino-2-oxo-1H-1,4-benzo[f]diazepine and 0.6 g of 5% ruthenium on carbon in 60 cm³ of methanol.After treatment, 0.77 g of(RS)-3-amino-1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzo[f]-diazepine is obtained in the form of a solid foam which is used assuch in the subsequent syntheses.

1-(N,N-Diethylcarbamoylmethyl)-2,3-dihydro-5-(2-fluorophenyl)-3-hydroxyimino-2-oxo-1H-1,4-benzo[f]diazepine can be obtained as in Example 5 for the preparation of1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-3-hydroxyimino-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepine, but starting from 5.7 g of1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzo[f]diazepine, 3.47 g of potassium tert-butoxide and 2.3 cm³ of isopentylnitrite in 200 cm³ of toluene. After treatment, 5.1 g of1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-5-(2-fluorophenyl)-3-hydroxyimino-2-oxo-1H-1,4-benzo[f]diazepine melting at 190° C. are obtained.

1-(N,N-Diethylcarbamoylmethyl)-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzo[f]diazepine can be obtained as in Example 5 for the preparation of1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepine, but starting from 5.08 g of2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzo [f]diazepine, 3.43 gof N,N-diethyl-2-chloroacetamide, 0.33 g of potassium iodide and 8.3 gof potassium carbonate in 60 cm³ of dry dimethylformamide. Aftertreatment, 5.8 g of1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzo[f]diazepineare obtained in the form of a solid foam which is used as such in thesubsequent syntheses.

2,3-Dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzo[f]diazepine can beprepared according to the method described by L. H. STERNBACH, R. I.FRYER, W. METLESICS, E. REEDER; G. SACH, G. SAUCY and A. STEMPEL, J.Org. Chem., 27, 3788-3796 (1962).

EXAMPLE 15

Working as in Example 1, but starting from 1.4 g of tert-butyl(RS)-{4-{3-[2,3-dihydro-1-(3,3-dimethylpiperidino)carbonylmethyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetateand 5.6 cm³ of trifluoroacetic acid, 0.59 g of(RS)-{4-{3-[2,3-dihydro-1-(3,3-dimethylpiperidino)carbonylmethyl2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid melting at 214° C. is obtained.

tert-Butyl(RS)-{4-{3-[2,3-dihydro-1-(3,3-dimethylpiperidino)carbonylmethyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetatecan be prepared in a manner analogous to that described in Example 1 forthe preparation of tert-butyl(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3yl]ureido}phenylthio}acetate, but starting from 1.64 g of(RS)-3-amino-2,3-dihydro-1-(3,3-dimethylpiperidino)carbonylmethyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepineand 1.1 g of tert-butyl (4-isocyanatophenylthio)acetate. 1.42 g oftert-butyl(RS)-{4-{3-[2,3-dihydro-1-(3,3-dimethylpiperidino)carbonylmethyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetateare thus obtained in the form of a solid which is used as such in thesubsequent syntheses.

tert-Butyl (4-isocyanatophenylthio)acetate can be prepared in a manneranalogous to that described in Example 1 for the preparation oftert-butyl (3-isocyanatophenylthio)acetate, but starting from 3.1 g oftert-butyl (4-aminophenylthio)acetate, 1.6 cm³ of trichloromethylchloroformate and 0.26 g of carbon. 2.3 g of tert-butyl(4-isocyanatophenylthio)acetate are thus obtained in the form of an oilwhich is used as such in the subsequent syntheses.

tert-Butyl (4-aminophenylthio)acetate can be prepared in a manneranalogous to that described in Example 1 for the preparation oftert-butyl (3-aminophenylthio)acetate, but starting from 5 g of4-aminothiophenol and 7.8 cm³ of tert-butyl bromoacetate. 7.45 g oftert-butyl (4-aminophenylthio)acetate are obtained in the form of an oilwhich is used as such in the subsequent syntheses.

EXAMPLE 16

Working as in Example 3, but starting from 0.8 g of ethyl(E)-(RS)-{3-{3-[2,3-dihydro-1-(3,3-dimethylpiperidino)carbonylmethyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}-2-propenoateand 1.6 cm³ of a normal aqueous solution of sodium hydroxide, 0.51 g of(E)-(RS)-3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(3,3-dimethylpiperidino)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}-2-propenoicacid melting at 216° C. is obtained.

(E)-(RS)-{3-{3-[2,3-Dihydro-1-(3,3-dimethylpiperidino)carbonylmethyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}-2-propenoatecan be prepared in a manner analogous to that described in Example 3 forthe preparation of ethyl(E)-(RS)-3-{3-{3-[1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}-2-propenoate,but starting from 1.7 g of(RS)-3-amino-2,3-dihydro-1-(3,3-dimethylpiperidino)carbonylmethyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepineand 0.9 g of ethyl 3-(3-isocyanatophenyl)-2-propenoate. 0.85 g of(E)-(RS)-{3-{3-[2,3-dihydro-1-(3,3-dimethylpiperidino)carbonylmethyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}-2-propenoateis thus obtained in the form of a solid which is used as such in thesubsequent syntheses.

EXAMPLE 17

Working as in Example 1, but starting from 2 g of tert-butyl(RS)-{4-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetateand 8 cm³ of trifluoro-acetic acid, 1.06 g of(RS)-{4-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid melting at 190° C. are obtained.

tert-Butyl(RS)-{4-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetatecan be prepared in a manner analogous to that described in Example 1 forthe preparation of tert-butyl(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetate,but starting from 6.3 g of(RS)-3-amino-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepineand 5.1 g of tert-butyl (4-isocyanatophenylthio)acetate. 2 g oftert-butyl(RS)-{4-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetateare thus obtained in the form of a solid which is used as such in thesubsequent syntheses.

EXAMPLE 18

Working as in Example 10, but starting from 2 g of(RS)-3-isocyanato-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepineand 2.9 g of tetrabutylammonium (RS)-1-(3-aminophenyl)ethanesulphonate,1.4 g of a mixture of isomers of potassium(RS)-1-{3-[3-(RS)-2,3-dihydro-2-oxo-5-phenyl-1-methyl-1H-1,4-benzo[f]diazepin-3-yl)ureido]phenyl}ethanesulphonate melting at250° C. are obtained.

Tetrabutylammonium (RS)-1-(3-aminophenyl)ethanesulphonate can beprepared as described in Example 2 for the preparation oftetrabutylammonium 3-aminophenylmethanesulphonate, but starting from 21g of tetrabutylammonium (RS)-1-(3-nitrophenyl)ethanesulphonate and 0.9 gof 5% palladium on carbon in 300 cm³ of ethanol. After treatment, 19 gof tetrabutylammonium (RS)-1-(3-aminophenyl)ethanesulphonate areobtained in the form of an oil which is used as such in the subsequentsyntheses.

Tetrabutylammonium (RS)-1-(3-nitrophenyl)ethanesulphonate can beprepared in the following manner: a mixture of 10.4 g of(RS)-3-(1-bromoethyl)nitrobenzene and 8.5 g of sodium hydrogensulphitein 109 cm³ of water is stirred at a temperature near to 70° C. for twohours. After cooling to a temperature near to 20° C., the solution ispoured into one liter of an aqueous solution of 89 g oftetrabutylammonium hydrogensulphate and extracted with three times 100cm³ of dichloromethane. The extracts are combined, washed with 50 cm³ ofwater, dried over magnesium sulphate and concentrated under reducedpressure. 21 g of tetrabutylammonium(RS)-1-(3-nitrophenyl)ethanesulphonate are thus obtained in the form ofan oil which is used as such in the subsequent syntheses.

(RS)-3-(1-Bromoethyl)nitrobenzene can be prepared according to themethod described by T. Y. SHEN, N. P. JENSEN, D. H. MINSKER, patent DE2,331,292.

(RS)-2,3-Dihydro-3-isocyanato-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepinecan be prepared in a manner analogous to that described in Example 10for the preparation of(RS)-2,3-dihydro-3-isocyanato-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepine,but starting from 2 g of(RS)-3-amino-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepine,0.09 g of carbon and 0.91 cm³ of trichloromethyl chloroformate. 2.13 gof(RS)-2,3-dihydro-3-isocyanato-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepineare thus obtained in the form of an oil which is used as such in thesubsequent syntheses.

EXAMPLE 19

Working as in Example 1, but starting from 1 g of tert-butyl(+)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl)ureido}phenylthio}acetateand 4 cm³ of trifluoroacetic acid, 0.6 g of(+)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid is obtained whose rotary power is [α]_(D) ²⁰ =+33.7° (c=0.994;methanol).

tert-Butyl(+)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl)ureido}phenylthio}acetatecan be obtained in the following manner: 2 g of tert-butyl(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetateare separated by high performance liquid chromatography on 400 g ofsupport formed of silica coated with cellulosetris(3,5-dimethylphenyl)carbamate prepared according to J. Amer. Chem.Soc., 106, 5357 (1984) and contained in a column of length 23 cm anddiameter 6 cm with ethanol as the mobile phase at a rate of 35 cm³/minute, eluting successively:

1 g of tert-butyl(+)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetatewhose rotatory power is [α]_(D) ²⁰ =+32.6° (c=0.994; methanol), then

0.840 g of a mixture which is recycled under the same conditions to give0.7 g of tert-butyl(-)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl-thio}acetatewhose rotatory power is [α]_(D) ²⁰ =-32.6° (c=0.614; methanol).

EXAMPLE 20

Working as in Example 1, but starting from 0.7 g of tert-butyl(-)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)-carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}-phenylthio}acetateand 3 cm³ of trifluoroacetic acid, 0.4 g of(-)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid whose rotatory power is [α]_(D) ²⁰ =-33.7° (c=0.961; methanol) isobtained.

EXAMPLE 21

Working as in Example 1, but starting from 0.4 g of a mixture of isomersof tert-butyl{3-{3-[(RS)-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylsulphinyl}acetateand 3 cm³ of trifluoroacetic acid, after recrystallization inisopropanol, 0.138 g of a mixture of isomers of(RS)-{3-{3-[(RS)-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylsulphinyl}aceticacid melting at 180° C. is obtained.

The mixture of isomers of tert-butyl(RS)-{3-{[(RS)-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylsulphinyl}acetatecan be obtained in the following manner: a solution of 3.7 g of Oxone®in 22 cm³ of water is added to a solution of 2 g of tert-butyl(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetatein 16 cm³ of methanol. The suspension is stirred for 16 hours at atemperature near to 20° C. and filtered, and the solid is washed withtwo times 10 cm³ of water and then ten times 10 cm³ of diethyl ether. Bychromatography on silica (eluent: ethyl acetate), the following areeluted successively:

1.05 g of tert-butyl(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetatein the form of a solid which is used as such in the subsequentsyntheses, and then

0.4 g of a mixture of isomers of(RS)-{3-{[(RS)-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylsulphinyl}acetatein the form of a solid which is used as such in the subsequentsyntheses.

EXAMPLE 22

Working as in Example 1, but starting from 1 g of tert-butyl(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylsulphonyl}acetateand 8 cm³ of trifluoroacetic acid, 0.61 g of(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylsulphonyl}aceticacid melting at 210° C. is obtained.

EXAMPLE 23

A solution of 0.091 g of lithium hydroxide in 11 cm³ of water is added,at a temperature near to 20° C., to a suspension of 1.4 g of a mixtureof isomers of ethyl2-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}propionatein 140 cm³ of ethanol. The reaction is stirred for 72 hours at atemperature near to 20° C., and then concentrated under reducedpressure. The residue is diluted with 50 cm³ of water and brought to pH1 with a 1N aqueous solution of hydrochloric acid. The solid whichprecipitates is filtered, washed with two times 10 cm³ of water and thenten times 10 cm³ of diethyl ether. After recrystallization in methanoland crushing in acetonitrile, 0.64 g of a mixture of isomers of(RS)-2-{3-{3-[(RS)-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}propionicacid melting at 184° C. is obtained.

The mixture of isomers of ethyl2-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}propionatecan be obtained in a manner analogous to that described in Example 1 forthe preparation of tert-butyl(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}propionate,but starting from 1.6 g of(RS)-3-amino-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepineand 1.1 g of ethyl 2-(3-isocyanatophenylthio)propionate. 1.7 g of amixture of isomers of ethyl2-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}-propionateare thus obtained in the form of a solid which is used as such in thesubsequent syntheses.

Ethyl 2-(3-isocyanatophenylthio)propionate can be obtained in a manneranalogous to that described in Example 1 for the preparation oftert-butyl (3-isocyanatophenylthio)acetate, but starting for 1 g ofethyl 2-(3-aminophenylthio)propionate, 0.54 cm³ of trichloromethylchloroformate and 0.09 g of carbon. 1.18 g of ethyl2-(3-isocyanatophenylthio)propionate are thus obtained in the form of anoil which is used as such in the subsequent syntheses.

Ethyl 2-(3-aminophenylthio)propionate can be prepared in a manneranalogous to that described in Example 1 for the preparation oftert-butyl (3-aminophenylthio)acetate, but starting from 9.25 g of3-aminothiophenol and 18.5 cm³ of ethyl2-trifluoromethylsulphonyloxypropionate and 10.2 g of potassiumcarbonate in 200 cm³ of acetonitrile. 4.04 g of ethyl2-(3-aminophenylthio)propionate are thus obtained in the form of an oilwhich is used as such in the subsequent syntheses.

Ethyl 2-trifluoromethylsulphonyloxypropionate can be prepared accordingto the method described by U. BURKARD, F. EFFENBERGER, Chem. Ber., 119,1594 (1986).

EXAMPLE 24

2.74 g of tert-butyl(RS)-{3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetateare dissolved slowly in 12 cm³ of trifluoroacetic acid. After stirringfor 1 hour at a temperature near to 20° C., 50 cm³ of methanol are addedand the mixture is stirred for 18 hours at a temperature near to 20° C.A suspension is obtained which is filtered. The filtrate is evaporatedto dryness under reduced pressure (2.7 kPa) to give an oil which ischromatographed on a column of diameter 4 cm containing 600 cm³ ofsilica, eluting first with 500 cm³ of dichloromethane and then with adichloromethane/methanol mixture (93:3 by volume) and collectingfractions of 125 cm³. The fractions between 2625 and 3125 cm³ arecombined and evaporated to dryness to give 1.4 of solid. Byrecrystallization in 50 cm³ of aqueous methanol (80:20 by volume), 0.93g of tert-butyl(RS)-{3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}acetateis obtained in the form of a white solid melting at 198° C.

EXAMPLE 25

The reaction is carried out as in Example 11, but starting from 2 g of(RS)-1-(N,N-diethylaminocarbonylmethyl)-2,3-dihydro-3-isocyanato-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepineand 0.92 g of N-{(3-aminophenyl)methyl}acetohydroxamic acid in 40 cm³ oftetrahydrofuran. After treatment, 0.24 g of(RS)-N-{{3-{3-[1-(N,N-diethylaminocarbonylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}methyl}acetohydroxamicacid is obtained in the form of a white solid melting at 186° C.

N-{(3-Amino-phenyl)methyl}acetohydroxamic acid can be prepared asdescribed in Example 2 for the preparation of tetrabutylammonium3-aminophenylsulphonate, but starting from 1.92 g ofN-{(3-nitrophenyl)methyl}-acetohydroxamic acid and 0.2 g of 10%palladium on carbon in 100 cm³ of methanol. After treatment, 1.73 g ofN-{(3-aminophenyl)methyl}acetohydroxamic acid are obtained in the formof an oil which is used as such in the subsequent syntheses.

N-{(3-Nitrophenyl)methyl}acetohydroxamic acid can be obtained in thefollowing manner: 22 cm³ of an 17N aqueous solution of ammonia are addedat a temperature near to 25° C. to a solution of 3.55 g ofN-acetoxy-N-{(3-nitrophenyl)methyl}acetamide in 120 cm³ of methanol. Thereaction mixture is stirred for two hours at a temperature near to 25°C., and then concentrated under reduced pressure. The residue isdissolved in 100 cm³ of a saturated aqueous solution of sodium chloride,dried over magnesium sulphate and concentrated under reduced pressure.2.46 g of N-{(3-nitrophenyl)methyl}acetohydroxamic acid melting at 80°C. are thus obtained.

N-Acetoxy-N-{(3-nitrophenyl)methyl}acetamide can be obtained in thefollowing manner: a solution of 3.35 g ofN-{(3-nitrophenyl)methyl}hydroxylamine in 8 cm³ of acetic anhydride and80 cm³ of acetic acid is heated to reflux for 3 hours. After cooling toa temperature near to 25° C., the reaction mixture is concentrated underreduced pressure. The residue is dissolved in 100 cm³ of diethyl etherand the organic phase is washed with 50 cm³ of a saturated aqueoussolution of sodium chloride, dried over magnesium sulphate andconcentrated under reduced pressure. 3.55 g ofN-acetoxy-N-{(3-nitrophenyl)methyl}acetamide are thus obtained in theform of an oil which is used as such in the subsequent syntheses.

N-{(3-Nitrophenyl)methyl}hydroxylamine can be obtained in the followingmanner: 3.78 g of sodium cyanoborohydride are added in portions in thecourse of two hours at a temperature near to 25° C. to a solution of 5 gof 3-nitrobenzaldoxime in 120 cm³ of acetic acid. The reaction mixtureis stirred for 16 hours at a temperature near to 25° C., and then pouredinto a mixture of 500 cm³ of ethyl acetate and 150 cm³ of a 30% aqueoussolution of potassium hydroxide. The organic phase is separated bydecantation and the aqueous phase is extracted with three times 500 cm³of ethyl acetate. The organic phases are combined, dried over magnesiumsulphate and concentrated under reduced pressure. The residue ispurified by chromatography on 200 cm³ of silica [eluentdichloromethane/methanol (98:2 by volume)]. The fractions containing theexpected product are combined and concentrated under reduced pressure.3.43 g of N-{(3-nitrophenyl)methyl}hydroxylamine are thus obtained inthe form of an oil which is used as such in the subsequent syntheses.

The medicaments according to the invention are made up by a compound offormula (I) in free form or in the form of a salt, in the pure state orin the form of a composition in which it is combined with any otherpharmaceutically compatible product, which can be inert orphysiologically active. The medicaments according to the invention canbe employed orally, parenterally, rectally or topically.

Solid compositions for oral administration which can be used aretablets, pills, powders (gelatine capsules, cachets) or granules. Inthese compositions, the active principle according to the invention ismixed with one or more inert diluents, such as starch, cellulose,sucrose, lactose or silica, under a stream of argon. These compositionscan also comprise substances other than the diluents, for example one ormore lubricants such as magnesium stearate or talc, a colorant, acoating (coated tablets) or a glaze.

Liquid compositions for oral administration which can be used aresolutions, suspensions, emulsions, syrups and pharmaceuticallyacceptable elixirs containing inert diluents such as water, ethanol,glycerol, vegetable oils or liquid paraffin. These compositions cancomprise substances other than the diluents, for example wetting,sweetening, thickening, flavoring or stablizing products.

The sterile compositions for parenteral administration may preferably beaqueous or non-aqueous solutions, or suspensions or emulsions. Thesolvent or vehicle employed can be water, propylene glycol, polyethyleneglycol, vegetable oils, in particular olive oil, injectable organicesters, for example ethyl oleate, or other suitable organic solvents.These compositions can also contain adjuvants, in particular wetting,isotonicizing, emulsifying, dispersing and stabilizing agents.Sterilization can be effected in several ways, for example by sterilefiltration, by incorporating sterilizing agents in the composition, byirradiation or by heating. The compositions can also be prepared in theform of sterile solid compositions which can be dissolved at the time ofuse in sterile water or any other injectble sterile medium.

Compositions for rectal administration are suppositories or rectalcapsules which contain, apart from the active product, excipients suchas cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Compositions for topical administration may be, for example, creams,lotions, eye lotions, mouthwashes, nasal drops or aerosols.

In human therapy, the compounds according to the invention areparticularly useful in the treatment and prevention of disordersconnected with CCK and gastrin at the level of the nervous system andthe gastrointestinal system. These compounds can thus be used in thetreatment and the prevention of psychoses, panic attacks, anxietydisorders, Parkinson's disease, tardive dyskinesia, irritable bowelsyndrome, acute pancreatitis, ulcers, disorders of intestinal motility,certain tumors sensitive to CCK, memory disorders, as analgesics, as apotentiator of the analgesic activity of narcotic and non-narcoticanalgesic medicaments, in weaning from chronic treatments or drug andalcohol abuse, as an appetite regulator and to control the constrictionof the pupil of the eye.

The doses depend on the effect sought after, on the duration of thetreatment and on the administration route used; they are generallybetween 0.05 g and 1 g per day orally for an adult with unit dosesranging from 10 mg to 500 mg of active substance.

Generally, the physician will determine the appropriate dosage as afunction of the age, weight and all the other factors peculiar to thesubject to be treated.

The following examples illustrate the compositions according to theinvention:

EXAMPLE A

According to the usual technique, gelatine capsules filled with 50 mg ofactive product having the following composition are prepared:

    ______________________________________                                        (RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-                                                               50 mg                                                 1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-                                      benzo[f]diazepin-3-yl]ureido}phenylthio}-                                     acetic acid                                                                   Cellulose               18 mg                                                 Lactose                 55 mg                                                 Colloidal silica         1 mg                                                 Sodium carboxymethylstarch                                                                            10 mg                                                 Talc                    10 mg                                                 Magnesium stearate       1 mg                                                 ______________________________________                                    

EXAMPLE B

According to the usual technique, tablets filled with 50 mg of activeproduct having the following composition are prepared:

    ______________________________________                                        (RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-                                                                 50 mg                                               1-(3,3-dimethylpiperidino)carbonylmethyl-1H-1,4-                              benzo[f]diazepin-3-yl]ureido}phenylthio}-                                     acetic acid                                                                   Lactose                   104 mg                                              Cellulose                 40 mg                                               Polyvidone                10 mg                                               Sodium carboxymethylstarch                                                                              22 mg                                               Talc                      10 mg                                               Magnesium stearate         2 mg                                               Colloidal silica           2 mg                                               Mixture of hydroxymethylcellulose, glycerol                                                             245 mg                                              and titanium dioxide (72:3.5:24.5) q.s. 1                                     245 mg finished film-coated tablet                                            ______________________________________                                    

EXAMPLE C

An injectable solution containing 10 mg of active product having thefollowing composition id prepared:

    ______________________________________                                        (E)-(RS)-{3-[1-(N-methyl-N-phenylcarbamoyl-                                                             10     mg                                           methyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-                                    benzo[f]diazepin-3-yl]ureido}-3-phenyl-2-                                     propenoic acid                                                                Benzoic acid              80     mg                                           Benzyl alcohol            0.06   cm.sup.3                                     Sodium benzoate           80     mg                                           95% ethanol               0.4    cm.sup.3                                     Sodium hydroxide          24     mg                                           Propylene glycol          1.6    cm.sup.3                                     Water q.s.                4      cm.sup.3                                     ______________________________________                                    

Although the invention has been described in conjunction with specificembodiments, it is evident that many alternatives and variations will beapparent to those skilled in the art in light of the foregoingdescription. Accordingly, the invention is intended to embrace all ofthe alternatives and variations that fall within the spirit and scope ofthe appended claims. The above references are hereby incorporated byreference.

We claim:
 1. A compound of formula: ##STR11## in which R₁ represents ahydrogen or halogen atom or an alkyl, alkoxy, alkylthio, nitro, hydroxylor cyano radical;R₂ represents an alkyl radical or a --CH(R₅)--CO--R₆chain in which R₅ represents a hydrogen atom or an alkyl, alkoxycarbonylor phenyl radical which is unsubstituted or substituted by at least onesubstituent selected from the group consisting of halogen atoms andalkyl, alkoxy, alkylthio and nitro radicals and R₆ represents an alkoxyradical, a cycloalkoxy radical which is unsubstituted or substituted byat least one alkyl radical, a cycloalkylalkoxy, phenylalkoxy,polyfluoroalkoxy or cinnamyloxy radical or an --NR₇ R₈ radical in whichR₇ and R₈, which are identical or different, represent a hydrogen atom,an alkyl radical, a phenyl radical which is unsubstituted or substitutedby at least one substituent selected from the group consisting ofhalogen atoms and alkyl, alkoxy and alkylthio radicals, acycloalkylalkyl, cycloalkyl, indanyl or phenylalkyl radical or else R₇and R₈, together with the nitrogen atom to which they are attached, forma heterocycle selected from the group consisting of piperidino,1-perhydroazepinyl, 1,2,3,6-tetrahydro-1-pyridyl,1,2,3,4-tetrahydro-1-quinolyl, 1-pyrrolidinyl,1,2,3,4-tetrahydro-2-isoquinolyl, morpholino, thiomorpholino and1-indolyl cyclic systems, these cyclic systems being unsubstituted orsubstituted by at least one alkyl radical; R₃ represents (a) a phenylradical substituted by at least one substituent selected from the groupconsisting of -alk-SO₃ H, -alk-PO₃ H₂, --CH═NOH, --CH═NO-alk-COOX,--S-alk-COOX, --SO₂ -alk-COOX, --CH═CH--COOX, -alk--CO-NHOH,--C(═NOH)--COOX, -alk-N(OH)--CO-alk, -alk-SO₂ H, --CH═CH--SO₃ H,--C(═COOX)═N--O--alk--COOX and tetrazolylalkyl radicals or a group offormula: ##STR12## or (b) a cyclic system of formula: ##STR13## in whichR₉ represents an ═NOX, ═NO-alk-COOX, ═CH--COOX, -alk-COOX, -alk-SO₂ H or-alk-SO₃ H radical, R₁₀ represents an oxygen or sulphur atom or amethylene or alkylimino radical and R₁₁ represents a methylene orethylene radical; R₄ represents a pyridyl or phenyl radicalunsubstituted or substituted by at least one substituent selected fromhalogen atoms and alkyl, alkoxy, hydroxyl, carboxyl, and nitro radicals;alk represents an alkyl or alkylene radical; and X represents a hydrogenatom or an alkyl radical; it being understood that the alkyl, alkyleneand alkoxy radicals and the alkyl, alkylene and alkoxy portions ofsubstituents contain 1 to 4 carbon atoms in a straight or branchedchain, and the cycloalkyl radicals and portions of substituents contain3 to 12 carbon atoms; a pharmaceutically acceptable salt thereof, aracemate thereof, or an enantiomer thereof, when they contain at leastone asymmetric center.
 2. A compound of formula (I) according to claim1, wherein R₁ represents a hydrogen atom, R₂ represents an alkyl radicalor -CH(R₅)COR₆ in which R₅ represents a hydrogen atom and R₆ representsan -NR₇ R₈ radical in which R₇ and R₈, together with the nitrogen atomto which they are attached, form a heterocycle selected from the groupconsisting of piperidino, 1-perhydroazepinyl,1,2,3,6-tetrahydro-1-pyridyl, 1,2,3,4-tetrahydro-1-quinolyl,1-pyrrolidinyl, 1,2,3,4-tetrahydro-2-isoquinolyl, morpholino,thiomorpholino and 1-indolyl cyclic systems, these cyclic systems beingunsubstituted or substituted by at least one alkyl radical,R₃ represents(a) a phenyl radical substituted by at least one substituent selectedfrom the radicals consisting of -alk-SO₃ H, -alk-PO₃ H₂, --CH═NOH,--CH═NO-alk-COOX, --S-alk-COOX, --SO-alk-COOX, --SO₂ -alk-COOX,--CH═CH--COOX, -alk-CO--NHOH, --C(═NOH)-COOX, -alk-N(OH)--CO-alk,-alk-SO₂ H, --CH═CH--SO₃ H, --C(COOX)═N--O-alk-COOX, tetrazolylalkyl anda group of formula: ##STR14## or (b) a cyclic system of formula:##STR15## in which R₉ represents an ═NOX, ═NO-alk-COOX, ═CH--COOX,-alk-COOX, -alk-SO₂ H or -alk-SO₃ H radical, R₁₀ represents an oxygen orsulphur atom or a methylene or alkylimino radical and R₁₁ represents amethylene or ethylene radical and R₄ represents a phenyl radical; apharmaceutically acceptable salt thereof, a racemate thereof, or anenantiomer thereof, when they contain at least one asymmetric center. 3.A compound of formula (I) according to claim 2, wherein--NR₇ R₈represents a 1-pyrrolodinyl or piperidino cyclic system, these cyclicsystems being unsubstituted or substituted by at least one alkylradical; a pharmaceutically acceptable salt thereof, a racemate thereof,or an enantiomer thereof, when they contain at least one asymmetriccenter.
 4. A compound selected from the followingcompounds:(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid,(RS)-3-[3-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl)ureido]phenylmethanesulphonicacid,(RS)-3-{3-[1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzo[f]diazepin-3-yl]-3-phenyl-2(E)propenoicacid,(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(3,3-dimethylpiperidino)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid,(RS)-{3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid,(E)-(RS)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl)-N'-(1-hydroxyimino-6-indanyl)urea,(E)-(RS)-2-{3,4-dihydro-6-[3-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl)ureido]-4-2H-benzopyranylidene}aceticacid,(E)-(RS)-3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}-2-phenylmethyleneaminooxyaceticacid,(RS)-2-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}-2-(carboxymethyloxyimino)aceticacid,(RS)-5-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}benzyl}-2,2-dimethyl-1,3-dioxane-4,6-dione,(E)-(RS)-2-{3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}ethylenesulphonicacid,(RS)-5-{3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}benzyl}tetrazole,(E)-(RS)-3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}-alpha-hydroxyiminophenylaceticacid,(RS)-{3-{3-[1-(N,N-diethylcarbamoylmethyl)-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid,(RS)-{4-{3-[2,3-dihydro-1-(3,3-dimethylpiperidino)carbonylmethyl-2-oxo-5-phenyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid,(E)-(RS)-3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(3,3-dimethylpiperidino)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenyl}-2-propenoicacid,(RS)-{4-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid, potassium(RS)-1-{3-[3-(RS)-2,3-dihydro-2-oxo-5-phenyl-1-methyl-1H-1,4-benzo[f]diazepin-3-yl)ureido]phenyl}ethanesulphonate,(+)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid,(-)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}aceticacid,(RS)-{3-{3-[(RS)-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylsulphinyl}aceticacid,(RS)-{3-{3-[2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylsulphonyl}aceticacid,(RS)-2-{3-{3-[(RS)-2,3-dihydro-2-oxo-5-phenyl-1-(1-pyrrolidinyl)carbonylmethyl-1H-1,4-benzo[f]diazepin-3-yl]ureido}phenylthio}propionicacid and their salts.
 5. A pharmaceutical composition for inhibiting CCKor gastrin, which comprises an effective amount of at least one compoundof formula (I) as claimed in claim 1 in combination with apharmaceutically acceptable carrier.
 6. A method for inhibiting CCK orgastrin which comprises administering to a host in need of saidinhibition an effective amount of a compound of formula (I) as claimedin claim 1.